Neoangiogenesis is involved in the pathophysiology of multiple myeloma and angiopoietins possibly contribute to myeloma-induced neovascularization. Bortezomib's antineoplastic potential includes an anti-angiogenic effect. We determined serum levels of angiopoietin-1 and angiopoietin-2 with ELISA pre- and post-bortezomib administration in 35 patients with relapsed/refractory multiple myeloma. Pre-bortezomib, serum angiopoietin-1 levels did not differ in patients and in healthy individuals, while serum angiopoietin-2 levels were elevated. Corresponding serum angiopoietin-1/angiopoietin-2 ratio was reduced in patients compared with controls. After treatment, serum angiopoietin-1 levels increased, while serum angiopoietin-2 levels decreased, therefore the angiopoietin-1/ angiopoietin-2 ratio increased and normalized. This increase was significant in patients who responded to treatment. In conclusion, angiopoietin-1/angiopoietin- 2 ratio normalization reflected response to bortezomib. ©2008 Ferrata Storti Foundation.

The majority of patients with indolent lymphomas relapse due to minimal residual disease (MRD). In the present study, we sought to determine whether by using rituximab consolidation, for eradication of MRD, following induction chemotherapy with fludarabine and mitoxantrone (FN) combination could improve the outcome of indolent lymphomas. Patients with indolent lymphoma received fludarabine 25mg/m2 Day 1-3 and mitoxantrone 10mg/m2 on Day 1 every 28 days. Patients who attained a response (complete response, CR or partial response, PR) received four weekly doses of Rituximab 375mg/m2 1 month and 3 months after completion of treatment. Forty-five patients were entered into this Phase II trial. The median follow-up time was 39 months. The median number of delivered cycles was 6. Fifty-three percent of patients attained a CR and 38% a PR for an overall response rate of 91%. One patient had stable disease, one had progression of the disease, whereas 2 were non-evaluable. After a median follow-up of 39 months, 32 of 46 patients (74%) are alive and disease-free. Grade III and IV toxicities included leucopenia (37%), neutropenia (28%), thrombocytopenia (7%), anemia (4%), and diarrhea (2%). Grade V toxicities included septic death in one patient and death due to hepatititis B reactivation 6 months after the last Rituximab dose in another patient. FN followed by R consolidation is a well-tolerated and active regimen in the treatment of patients with indolent lymphomas. Further follow-up is required to determine if these remissions are maintained.

The incidence of venous thromboembolism (VTE) is more than 1‰ annually in the general population and increases further in cancer patients. The risk of VTE is higher in multiple myeloma (MM) patients who receive thalidomide or lenalidomide, especially in combination with dexamethasone or chemotherapy. Various VTE prophylaxis strategies, such as low-molecular-weight heparin (LMWH), warfarin or aspirin, have been investigated in small, uncontrolled clinical studies. This manuscript summarizes the available evidence and recommends a prophylaxis strategy according to a risk-assessment model. Individual risk factors for thrombosis associated with thalidomide/lenalidomide-based therapy include age, history of VTE, central venous catheter, comorbidities (infections, diabetes, cardiac disease), immobilization, surgery and inherited thrombophilia. Myeloma-related risk factors include diagnosis and hyperviscosity. VTE is very high in patients who receive high-dose dexamethasone, doxorubicin or multiagent chemotherapy in combination with thalidomide or lenalidomide, but not with bortezomib. The panel recommends aspirin for patients with ≤1 risk factor for VTE. LMWH (equivalent to enoxaparin 40mg per day) is recommended for those with two or more individual/myeloma-related risk factors. LMWH is also recommended for all patients receiving concurrent high-dose dexamethasone or doxorubicin. Full-dose warfarin targeting a therapeutic INR of 2-3 is an alternative to LMWH, although there are limited data in the literature with this strategy. In the absence of clear data from randomized studies as a foundation for recommendations, many of the following proposed strategies are the results of common sense or derive from the extrapolation of data from many studies not specifically designed to answer these questions. Further investigation is needed to define the best VTE prophylaxis.

Objectives: To investigate potential prognostic and predictive factors in patients with androgen-independent prostate cancer (AIPC) treated with docetaxel chemotherapy. Methods: This analysis included 94 consecutive AIPC patients who were treated between March 2001 and May 2006 with biweekly docetaxel 45 mg/m2 (day 2) and estramustine 140 mg three dimes daily (days 1-3). Results: Prostate-specific antigen (PSA) responses were observed in 45 of 84 evaluable patients (53%), whereas objective responses were observed in 16 of 40 patients with measurable disease (40%). Median survival (OS) was 16.2 mo (95% confidence interval [CI], 12.9-19.4) and median time to PSA progression (TTP) 5.0 mo (95%CI, 3.6-7.1). OS was independently associated with pain score baseline PSA and weight loss. Patients with only extraosseous disease had higher PSA response rate (87% vs. 49%, p = 0.014) and superior TTP compared with patients with bone metastases with or without extraosseous disease (7.3 vs. 4.3 vs. 4 mo, p = 0.002). Concurrent bone and extraosseous metastases were associated with worse prognosis compared with each site alone (median OS: 12.3 vs.19 vs.18.3 mo, p = 0.007). Conclusions: Among patients with AIPC treated with biweekly docetaxel and estramustine, baseline PSA >100, existence of pain, weight loss, and simultaneous extraosseous and bone disease were associated with worse prognosis. Extraosseous metastases seem to be more sensitive than bone disease to this chemotherapy. © 2007 European Association of Urology.

Wegener's granulomatosis is a systemic necrotizing vasculitis that usually involves the kidneys, typically causing segmental necrotizing glomerulonephritis. An association between Wegener's granulomatosis and renal cell carcinoma was recently reported. We describe a case of Wegener's granulomatosis presenting as a renal mass in a 72-year-old woman. Histologic examination of the mass revealed granulomatous inflammation, an extremely rare manifestation of this disease. We also review the incidence of renal mass in Wegener's granulomatosis and highlight the importance of excluding the coexistence of renal cell carcinoma. © 2008 Elsevier Inc. All rights reserved.

Aurora kinases represent a family of serine/threonine kinases highly conserved during evolution, whose main function is to promote mitotic spindle assembly by regulating centrosome duplication and separation. Inhibition of Aurora kinase activity may lead to defects in centrosome function, misaligned sister chromatides, mitotic spindle malformation, problematic cytokinesis and eventually mitotic arrest. Aurora kinases are overexpressed in a variety of tumor cell lines, suggesting their potential role in tumorigenesis and indicating that they could represent an appealing target for molecular therapies. Extensive pre-clinical information supports the development of Aurora kinase inhibitors in specific tumor types and a number of these novel agents are currently being extensively studied in phase I and II clinical trials exhibiting an acceptable toxicity profile and promising clinical efficacy. The current study aims to provide a comprehensive overview of the development of Aurora kinases as molecular targets for anticancer therapy by focusing on their physiological role in mitosis, their implication in oncogenesis and the potential ways of inhibiting their activity. The main pre-clinical and clinical studies concerning Aurora kinase inhibitors currently under investigation are reported and important considerations for their future development are discussed. © 2007 Elsevier Ltd. All rights reserved.

Background: Bortezomib is a novel, first-in-class proteasome inhibitor that has improved outcomes in multiple myeloma. with manageable toxicities. Objective: To summarise the chemistry, pharmacokinetics and metabolism of bortezomib, and review its clinical efficacy and toxicity, including use in elderly patients, use in patients with renal impairment and/or a poor prognosis, and effects on bone metabolism. Methods: Literature search of bortezomib studies (within 10 years) and recent congress abstracts. Results/conclusions: Bortezomib has improved response rates, overall survival, and time to progression in relapsed or refractory disease, both as a single agent and as part of combination regimens. Promising results have also been reported with bortezomib combinations in frontline induction therapy. Patient subgroups where conventional approaches are inappropriate may also benefit, thereby expanding the therapeutic armamentarium against this debilitating disease. © 2008 Informa UK Ltd.

Although platinum-based chemotherapy remains the "standard" in advanced non small-cell lung cancer, not all patients-derive clinical benefit from such a treatment. Hence, the development of predictive biomarkers able to identify lung cancer patients who are most likely to benefit from cisplatin-based chemotherapy has become a scientific priority. Among the molecular pathways involved in DNA damage control after chemotherapy, the nucleotide excision repair (NER) is a critical process for the repair of DNA damage caused by cisplatin-induced DNA adducts. Many reports have explored the role of the excision repair cross-complementation group 1 enzyme (ERCC1) expression in the repair mechanism of cisplatin-induced DNA adducts in cancer cells. Using immunohistochemistry in resected tumors from patients included in the International Adjuvant Lung Cancer Trial, the study of important biomarkers showed that high ERCC1 protein expression was associated with improved survival in chemo-naïve patients. On the contrary, the benefit of adjuvant cisplatin-based chemotherapy was more profound in patients with low ERCC1 expression. In a prospective cohort studying mRNA expression in tumor biopsies from patients receiving customized therapy with cisplatin and gemcitabine depending on the molecular profile of the tumour, results showed that patients with low ERCC1 mRNA expression had a longer median survival compared to those with high expression. These data suggest the potent use of ERCC1 as a molecular predictor of clinical resistance to platinum-based chemotherapy in the adjuvant setting of NSCLC. Nevertheless, optimization of methodology, including standardization of technical procedures, as well as validation of ERCC1 protein expression in large prospective cohorts, seem necessary before any routine immunohistochemical validation of ERCC1 can be implemented in daily practice.

Background: The aim was to examine characteristics and treatment results of patients with mucosa-associated lymphoid tissue (MALT) non-Hodgkin's lymphomas. Patients and methods: Epidemiological and clinical features of 97 patients with MALT lymphoma from the Hellenic Cooperative Oncology Group registry were analysed retrospectively for their prognostic significance in progression-free survival (PFS) and overall survival (OS). Comparisons were made between patients with gastric and nongastric sites of primary lymphoma and between different therapeutic modalities. Results: Sixty-five patients presented with gastric and 32 with nongastric lymphomas. The most frequent locations of nongastric lymphomas were the bowel, lung and parotid. Gastric lymphomas occurred more frequently in males and younger patients compared with nongastric lymphomas. Seventy-four per cent of patients had early (Ann Arbor stages I-II) and 26% had advanced (stages III-IV) disease. The median PFS for the entire population was 44 months. At 5 years, 47% of patients were progression free and the OS rate was 80%. The most reliable prognostic factor for PFS and OS was the Ann Arbor stage; 5-year PFS was 67% versus 13% and 5-year OS 91% versus 51% for patients with early versus advanced disease, respectively (P < 0.001). Of the patients treated with chemotherapy only, 87% achieved an objective response and 71% complete response. Surgery did not offer survival benefit compared with chemotherapy in localised gastric lymphoma. Conclusion: MALT lymphomas represent a distinct disease entity with widespread extranodal origin, indolent clinical course and high chemosensitivity. Ann Arbor stage was the most reliable prognostic and predictive factor. © The Author 2007. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

We analyzed the presenting features and survival in 1689 patients with multiple myeloma aged younger than 50 years compared with 8860 patients 50 years of age and older. Of the total 10 549 patients, 7765 received conventional therapy and 2784 received high-dose therapy. Young patients were more frequently male, had more favorable features such as low International Staging System (ISS) and Durie-Salmon stage as well as less frequently adverse prognostic factors including high C-reactive protein (CRP), low hemoglobin, increased serum creatinine, and poor performance status. Survival was significantly longer in young patients (median, 5.2 years vs 3.7 years; P< .001) both after conventional (median, 4.5 years vs 3.3 years; P < .001) or high-dose therapy (median, 7.5 years vs 5.7 years; P = .04). The 10-year survival rate was 19% after conventional therapy and 43% after high-dose therapy in young patients, and 8% and 29%, respectively, in older patients. Multivariate analysis revealed age as an independent risk factor during conventional therapy, but not after autologous transplantation. A total of 5 of the 10 independent risk factors identified for conventional therapy were also relevant for autologous transplantation. After adjusting for normal mortality, lower ISS stage and other favorable prognostic features seem to account for the significantly longer survival of young patients with multiple myeloma with age remaining a risk factor during conventional therapy. © 2008 by The American Society of Hematology.

During the last decade several novel agents have been used in the management of patients with multiple myeloma. Immunomodulatory drugs and proteasome inhibitors exert their efficacy both directly by inducing apoptosis of myeloma cells and indirectly through the interruption of the interactions between myeloma and stromal cells in the bone marrow (BM) microenvironment. These interactions are crucial for myeloma cell growth and survival. The adherence of myeloma cells to BM stromal cells leads to the overproduction of several cytokines with angiogenic properties that enhance the survival and growth of myeloma cells through paracrine and autocrine loops. The correlation of these molecules with clinical features and survival of myeloma patients supports the importance of angiogenesis in the pathogenesis of the disease and reveals these cytokines as suitable targets for the development of novel anti-myeloma therapies. This review summarises all available preclinical and clinical data for the effect of novel agents that are used in myeloma therapy, such as thalidomide, lenalidomide, bortezomib and VEGF inhibitors, on angiogenesis, which is at least partially responsible for their remarkable anti-myeloma efficacy.

Background: A randomized phase III trial in high-risk breast cancer patients was conducted, to further explore the impact of dose-density in the adjuvant treatment for breast cancer. The safety analysis is presented. Patients and methods: From October 2000 until June 2005, 1121 node-positive patients were randomized to sequential dose-dense epirubicin 110 mg/m2 and paclitaxel (Taxol®, Bristol Myers-Squibb, Princeton, New Jersey, USA) 250 mg/m2 (group A), or concurrent epirubicin 83 mg/m2 and paclitaxel 187 mg/m2 (group B), both followed by three cycles of 'intensified' combination chemotherapy with cyclophosphamide, methotrexate and fluorouracil (CMF). Granulocyte colony-stimulating factor was given prophylactically with the dose-dense treatments. Results: Median dose intensity of epirubicin and paclitaxel was double in group A, as designed, with significantly less cycles administered at full dose (P < 0.001). Median cumulative dose of all drugs and total treatment duration, however, were identical between groups. Severe taxane-related toxic effects were more frequent in group A, while severe thrombocytopenia was low and present only in group A. There were no differences in the rates of other hematological toxic effects, including febrile neutropenia. The rates of secondary malignancies were low. Conclusion: Both regimens as used in the present study are well tolerated and safe. The rates of severe taxane-related toxic effects and thrombocytopenia, although low overall, are significantly increased with the dose-dense sequential regimen. © The Author 2007. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

Multiple sclerosis (MS) is the most common cause of neurological disability. Therapeutic plasma exchange (TPE) has been used in the management of patients with MS with equivocal efficacy. With this work we would like to present our experience with 10 patients (seven male and three female, mean age 34 years [range 27-53 years]) with secondary progressive MS, who were treated with immunomodulating agents and who also underwent TPE. The patients' expanded disability status scale (EDSS) score of entry to the study varied from 5.0 to 6.5. One year before study entry all patients showed a marked deterioration (12 months before starting TPE they had been rated 4.5-5.5 on the EDSS). TPE was performed three times a week for two weeks and thereafter once a week, or once a month for the stable patients. The machine used was the Cobe Spectra and albumin 5% was the replacement fluid. Peripheral veins were used in nine patients and indwelling vascular access was required in one patient. Eighteen months later, patients stopped taking the immunomodulating agent therapy and continued only with TPE. No side-effects occurred during the TPE session. After 36 months of TPE therapy, five patients were stabilized in their disability, while two patients showed a minor progression of the disease (an additional 0.5 degree in disability as determined by the EDSS). No relapses occurred during TPE. Three patients stopped the therapy: one patient because of persistent nausea and two patients for reasons unrelated to TPE. Periodic TPE was associated with reduced accumulation of neurological deficits (as documented by EDSS) in patients with secondary progressive MS. © 2008 International Society for Apheresis.

Renal failure is a common feature of multiple myeloma and a major management problem. However there is limited data regarding the reversibility of renal failure, the kinetics of serum creatinine and the safety of novel agents such as bortezomib when administered to newly diagnosed or relapsed/refractory patients with renal failure. Patients and Methods. We evaluated 20 consecutive patients with newly diagnosed or relapsed/refractory multiple myeloma and renal failure, defined as a serum creatinine ≥ 2 mg/dl. All patients received bortezomib with dexamethasone or in combination with other agents (thalidomide, doxorubicin or melphalan). Results. Reversal of renal failure was documented in 40% of all patients and the median time to reversal was 17 days. Moreover 10 patients (50%) had 50% decrease in serum creatinine and the median time to decrease was 35 days. Some decrease of creatinine was documented in 85% of patients. The objective response rate was 65%. Toxicities were similar to those seen in myeloma patients without renal failure. Conclusions. Bortezomib based regimens can be administered to myeloma patients with renal impairment and their toxicity and efficacy are similar to those observed in patients without renal impairment. Moreover, bortezomib-based regimens induce improvement of serum creatinine in most patients and reversal of renal failure in approximately one-third.

Objectives: Docetaxel is an effective first-line treatment for hormone-refractory prostate cancer. Nevertheless, the prognosis subsequent to progression after first-line therapy is poor and no second-line treatment has been established. Methods: A total of 34 patients with androgen-independent prostate cancer received doxorubicin, 30 mg/m2, every 2 weeks and ketoconazole daily, 400 mg orally every 8 hours. All patients had been treated with docetaxel and had disease progression within 6 months after completion of first-line treatment. Results: Of the 32 evaluable patients, 13 (43.7%, 95% confidence interval [CI] 26.3% to 62.3%) had a prostate-specific antigen (PSA) response, and 4 (28%, 95% CI 8.4% to 58.1%) of 14 patients with measurable disease had a response to therapy. The median time to progression (TTP) was 3.9 months (95% CI 2.0 to 5.9), and the median overall survival (OS) was 13 months (95% CI 8.7 to 17.3). Toxicity was mild, with only 4 cases of nonhematologic grade 3 or 4 toxicity. The most frequent toxicity was nail changes (33 of 34 patients), which was mainly grade 1 (30 cases). Conclusions: The combination of biweekly doxorubicin and ketoconazole is an effective, well-tolerated, second-line therapy for hormone-refractory prostate cancer. © 2008 Elsevier Inc. All rights reserved.

Background: Kallikreins, a subgroup of the serine protease enzyme family, are considered important prognostic biomarkers in cancer. Here, we sought to determine the prognostic value of kallikrein 7 (hk7) in ovarian cancer using a novel method of compartmentalized in situ protein analysis. Patients and methods: A tissue array composed of 150 advanced-stage ovarian cancers, uniformly treated with surgical debulking followed by platinum-paclitaxel (Taxol) combination chemotherapy, was constructed. For evaluation of kallikrein 7 protein expression, we used an immunofluorescence-based method of automated in situ quantitative measurement of protein analysis (AQUA). Results: Mean follow-up time ofthe cohort was 34.35 months. One hundred and twenty eight of 150 cases had sufficient tissue for AQUA. In univariate survival analysis, low tumor hk7 expression was associated with better outcome for overall survival (OS) and disease-free survival in 3 years (P values 0.032 and 0.037, respectively). In multivariate survival analysis, adjusting for well-characterized prognostic variables, low tumor hk7 expression level was the most significant predictor variable for OS (95% confidence interval 0.125-0.729, P = 0.007). Conclusions: High tumor hk7 protein expression is associated with inferior patient outcome in ovarian cancer. hk7 may represent a promising prognostic factor in ovarian cancer. © The Author 2008. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

Background: Cycloxygenase (COX)-2 has been associated with proliferation, apoptosis and angiogenesis in urothelial cancer. The prognostic significance of COX-2 in patients who received adjuvant chemotherapy for urothelial cancer was examined. Patients and Methods: Expression of COX-2, p53, ki67, β-catenin, vascular endothelial growth factor (VEGF) and microvessel density (MVD) were studied retrospectively in 59 patients with urothelial cancer (pT3, pT4, N+) who had undergone surgery. The patients had subsequently received adjuvant chemotherapy. Results: Thirty-eight out of 59 cases (64% ) were positive for COX-2. COX-2 was not associated either with progression-free survival (PFS) or overall survival (OS). MVD levels ≥47 were associated with longer median PFS compared with lower levels (not reached vs. 13 months [95% CI: 8-18], p=0.048). The median PFS for patients with β-catenin nuclear accumulation and COX-2 expression was 6 months (95% CI: 4-7) compared with 19 months (95% CI: 14-23) for neither or only one of these factors (p=0.018). Conclusion: MVD may be a useful indicator of relapse in high-risk urothelial cancer treated with adjuvant chemotherapy.

Purpose: There are major differences affecting genes in adenocarcinomas in ever and never smokers. However, data on whether mitogen-activated protein kinase (MAPK) activation state differs according to smoking status are limited. Experimental Design: Expression of activated extracellular signal - regulated kinases, c-Jun NH2-terminal kinases, and P38 enzymes (pP38) were evaluated by means of immunohistochemistry in 188 chemonaïve patients with surgically resected lung adenocarcinoma. Cell viability of the lung adenocarcinoma cell line HCC827 was studied after treatment with cisplatin or the P38 MAPK inhibitor SB 203580. Results: Thirty-seven of 44 never smokers [84%; 95% confidence intervals (95% CI), 70-92%] expressed high pP38 levels compared with 45 of 104 ever smokers (43%; 95% CI, 34-53%; P < 0.0001). The proportion of never smokers expressing high c-Jun NH2-terminal kinase levels (72%; 95% CI, 57-83%) was greater than that of ever smokers (53%; 95% CI, 44-62%; P = 0.03). The proportion of ever smokers expressing high extracellular signal - regulated kinase levels (51%; 95% CI, 42-59%) was similar to that of never smokers (57%; 95% CI, 42-71%; P = 0.47). Never smokers were 10.5 times (95% CI, 3.5-31.5) more likely to express high pP38 levels after adjustment for variables linked to smoking status, including age, sex, and histologic subtype. None of the activated MAPKs predicted for overall survival. Cell viability of HCC827 was significantly reduced after exposure to SB203580 alone or when combined with cisplatin. Conclusions: Life-long nonsmoking is associated with high activated P38 levels in patients with lung adenocarcinoma. Activated P38 can contribute to the viability of adenocarcinoma cells in never smokers, but is not predictive for overall survival. © 2008 American Association for Cancer Research.

Background: Cancer of unknown primary (CUP) lacks established therapy although it affects 3% of cancer patients. We evaluated the irinotecan- oxaliplatin combination (IROX regimen) in previously untreated patients with non-favorable subsets of unknown primary carcinomas. Methods: This was a multicenter phase-II trial. Protocol treatment consisted of oxaliplatin 80 mg/m2 followed by irinotecan 160 mg/m2 administered every 3 weeks. The primary end points were response rate and toxicity, and secondary end points were time to progression and survival. Results: Forty-seven patients with liver, bone or multiple visceral metastases entered into the trial and received a median 6 chemotherapy cycles (1-11). The regimen was very well tolerated with one febrile neutropenia case and six cases with diarrhea grade 3 (16%). In intent-to-treat analysis the tumor response rate was 13% (95% CI = 4.8-25.7%) and 12 patients (27%, 95%CI 13.9-40.4%) had at least 4 months' duration of disease stabilization. The median time to progression was 2.7 months and the median survival was 9.5 months, with 40% of patients alive at 1 year. Conclusions: The IROX regimen demonstrated similar efficacy and a favorable toxicity profile compared to other more toxic chemotherapy combinations in patients with poor-prognosis CUP. © 2007 Springer-Verlag.

Objective: Taxanes, anthracyclines, and platinum compounds represent the chemotherapeutic agents with the greatest activity in metastatic endometrial carcinoma. We administered the combination of paclitaxel, epirubicin and carboplatin to patients with metastatic or recurrent carcinoma of the endometrium to evaluate its activity and to define its toxicity. Methods: Sixty-three consecutive patients were treated on an outpatient basis with epirubicin 50 mg/m2, followed by paclitaxel 150 mg/m2, administered intravenously over a 3-h period. Subsequently, the patients received carboplatin at AUC of 5. The chemotherapy was repeated every 3 weeks with granulocyte colony-stimulating factor (G-CSF) support for a maximum of six courses. Results: Response was assessed among 56 eligible patients. Thirty-six (63.2%) patients achieved objective clinical response (95% CI, 50.6-75.7%) including 14 (24.6%) complete and 22 (38.6%) partial responses. The median duration of response was 7.9 months, and the median times to progression and survival for all patients were 7.8 and 13.8 months, respectively. Grade 3 or 4 neutropenia occurred in 9 (15.5%) patients but only 3 episodes of neutropenic fever were encountered. Grade 2 or 3 neurotoxicity was observed in 19% of patients. Two patients died of sudden cardiac death 10 and 14 days after the administration of the first chemotherapy cycle, respectively, but these deaths were not clearly treatment related. Conclusions: The combination of paclitaxel, epirubicin and carboplatin with G-CSF support appears active in patients with metastatic or recurrent carcinoma of the endometrium. © 2008 Elsevier Inc. All rights reserved.

Renal failure is a frequent complication in patients with multiple myeloma (MM) that causes significant morbidity. In the majority of cases, renal impairment is caused by the accumulation and precipitation of light chains, which form casts in the distal tubules, resulting in renal obstruction. In addition, myeloma light chains are also directly toxic on proximal renal tubules, further adding to renal dysfunction. Adequate hydration, correction of hypercalcemia and hyperuricemia and antimyeloma therapy should be initiated promptly. Recovery of renal function has been reported in a significant proportion of patients treated with conventional chemotherapy, especially when high-dose dexamethasone is also used. Severe renal impairment and large amount of proteinuria are associated with a lower probability of renal recovery. Novel agents, such as thalidomide, bortezomib and lenalidomide, have significant activity in pretreated and untreated MM patients. Although there is limited experience with thalidomide and lenalidomide in patients with renal failure, data suggest that bortezomib may be beneficial in this population. Clinical studies that have included newly diagnosed and refractory patients indicate that bortezomib-based regimens may result in rapid reversal of renal failure in up to 50% of patients and that full doses of bortezomib can be administered without additional toxicity.

Lenalidomide is an immunomodulatory drug, structurally related to thalidomide, with pleiotropic activity including antiangiogenic and antineoplastic properties. It is the product of advances in our understanding of the biology of myeloma cells, their interactions with the microenvironment and of the underlying molecular pathways. In preclinical and clinical studies, lenalidomide was more potent and less toxic than thalidomide. Subsequent phase II and III studies confirmed the activity of lenalidomide either as a single agent or in combination with dexamethasone in relapsed or refractory myeloma patients, whereas combinations with chemotherapy induce high response rates and durable remissions. Lenalidomide has been used successfully as an upfront treatment either with high or low dose dexamethasone or with melphalan and prednisone, resulting in high overall response and complete response rates and excellent 1-year survival. Lenalidomide causes less neuropathy than thalidomide; however, the risk of thromboembolism is high, especially in patients treated with lenalidomide and steroids. In this review, we summarize the mechanisms of action, toxicity and clinical activity, and the current role of lenalidomide in patients with multiple myeloma or other related plasma cell disorders.

Primary objective: Granulocyte-colony stimulating factor (G-CSF) is used for the mobilization of bone marrow and endothelial progenitor cells, though G-CSF-induced inflammation may cause endothelial dysfunction. We examined the effects of G-CSF on endothelium, C-reactive protein (CRP), tumour necrosis factor-α (TNF-α) and anti-inflammatory cytokines namely interleukin 10 (IL-10). Research design: We studied 60 women with breast cancer, who were randomized to either subcutaneous G-CSF (5 μg/kg), o.d. for 5 days after adjuvant chemotherapy (n = 40) or placebo (n = 20). Experimental interventions: We measured flow-mediated dilatation (FMD%) of the brachial artery by ultrasonography, CRP, TNF-α, IL-10 and the ratio TNF-α/IL-10 blood levels before, 2-h and 5-days after the G-CSF or placebo treatment. Main outcomes and results: There was a greater increase of FMD, IL-10 and reduction of TNF-α/IL-10, 2 h and 5 days after the G-CSF treatment compared to placebo. Although, CRP and TNF-α were higher, TNF-α/IL-10 was lower at the end of G-CSF treatment compared to placebo. Improvement of FMD was related to changes of IL-10 and TNF-α/IL-10. Conclusions: Treatment with G-CSF improves endothelial function in vivo, possibly by shifting the balance between the pro- and anti-inflammatory cytokines.

Background: The standard treatment for patients with multiple myeloma who are not candidates for high-dose therapy is melphalan and prednisone. This phase 3 study compared the use of melphalan and prednisone with or without bortezomib in previously untreated patients with multiple myeloma who were ineligible for high-dose therapy. Methods: We randomly assigned 682 patients to receive nine 6-week cycles of melphalan (at a dose of 9 mg per square meter of body-surface area) and prednisone (at a dose of 60 mg per square meter) on days 1 to 4, either alone or with bortezomib (at a dose of 1.3 mg per square meter) on days 1, 4, 8, 11, 22, 25, 29, and 32 during cycles 1 to 4 and on days 1, 8, 22, and 29 during cycles 5 to 9. The primary end point was the time to disease progression. Results: The time to progression among patients receiving bortezomib plus melphalan-prednisone (bortezomib group) was 24.0 months, as compared with 16.6 months among those receiving melphalan-prednisone alone (control group) (hazard ratio for the bortezomib group, 0.48; P<0.001). The proportions of patients with a partial response or better were 71% in the bortezomib group and 35% in the control group; complete-response rates were 30% and 4%, respectively (P<0.001). The median duration of the response was 19.9 months in the bortezomib group and 13.1 months in the control group. The hazard ratio for overall survival was 0.61 for the bortezomib group (P=0.008). Adverse events were consistent with established profiles of toxic events associated with bortezomib and melphalan-prednisone. Grade 3 events occurred in a higher proportion of patients in the bortezomib group than in the control group (53% vs. 44%, P=0.02), but there were no significant differences in grade 4 events (28% and 27%, respectively) or treatment-related deaths (1% and 2%). Conclusions: Bortezomib plus melphalan-prednisone was superior to melphalan-prednisone alone in patients with newly diagnosed myeloma who were ineligible for high-dose therapy. (ClinicalTrials.gov number, NCT00111319.). Copyright © 2008 Massachusetts Medical Society. All rights reserved.

Introduction: The combination of Carboplatin and Paclitaxel is considered the standard of care as initial chemotherapy for Advanced Ovarian Cancer (AOC). We compared this regimen with the combination of Cisplatin, Paclitaxel and Doxorubicin. Patients and methods: Patients with AOC were randomised to either six courses of Paclitaxel 175 mg/m2 plus Carboplatin 7AUC or Paclitaxel at the same dose plus Cisplatin 75 mg/m2 plus Doxorubicin 40 mg/m2. Results: Analysis was performed on 451 patients. The treatment groups were well balanced with regard to patient and disease characteristics. Performance status (PS) was better in the anthracycline arm. In terms of severe toxicity, the only significant difference between the two groups was the development of febrile neutropaenia in the anthracycline arm. Overall response rate was similar in both groups. With a median follow-up of 57.5 months, a marginal significance towards improved Progression-Free Survival (PFS) was noted in favour of the anthracycline arm, whilst there was no difference in overall survival. In multivariate analysis the hazard of disease progression at any time was significantly decreased by 25.5% for patients of the anthracycline arm. Conclusion: The combination of Cisplatin, Paclitaxel and Doxorubicin demonstrates a marginal PFS improvement, but no additional survival benefit when compared with the standard Carboplatin/Paclitaxel regimen. © 2008 Elsevier Ltd. All rights reserved.

Background: A number of studies have shown that absence of myelotoxicity during chemotherapy is associated with worse outcome for various types of cancer, including carcinoma of the breast. The aim of this study was to determine whether myelosuppression in patients being treated with chemotherapy for advanced breast cancer has an impact on their prognosis. Patients and Methods: A retrospective review was conducted of a series of 475 patients with advanced breast cancer enrolled in two randomised trials, who received first-line chemotherapy. The impact of severe (grade 3 or 4) hematological toxicity on survival and time to disease progression was assessed. Results: When severe myelotoxicity was evaluated as a whole, a significant negative association for time to disease progression and a trend for a worse survival were demonstrated. In multivariate analysis, hematological toxicity retained its significance as an independent negative prognostic factor for time to disease progression. Conclusion: Our findings do not confirm the results of previous studies which have demonstrated a better outcome for patients experiencing hematological toxicity during treatment.

Background: Primary fallopian tube carcinoma (PFTC) is a rare gynecologic malignancy with very few data existing on the activity of the combination of paclitaxel with a platinum analogue as adjuvant chemotherapy. Methods: We retrospectively analyzed 41 consecutive patients with PFTC who were treated postoperatively with paclitaxel- and platinum-containing chemotherapy regimens. Results: We observed 12 (63.2%) complete and 6 (31.6%) partial responses among 19 patients with measurable disease. The median time to disease progression (TTP) for all patients was 68 months. The median overall survival (OS) for all patients has not been reached yet. The median TTP was 84 months for patients with stage I/II disease and 34 months for patients with advanced disease (p = 0.017). Median OS has not been reached yet for patients with stage I/II PFTC, while it was 63.8 months for patients with stage III/IV disease (p = 0.002). Furthermore, OS has not been reached yet for patients with optimally debulked tumors, while it was 34.1 months for patients with residual disease >2 cm (p < 0.0001). Conclusion: Adjuvant platinum- and paclitaxel-based chemotherapy should be regarded as the standard treatment in patients with PFTC. Early stage disease and optimal debulking are associated with improved TTP and OS. Copyright © 2008 S. Karger AG.

Objective: Taxanes, and platinum compounds represent the chemotherapeutic agents with the greatest activity in metastatic endometrial carcinoma. We administered the combination of paclitaxel, topotecan and carboplatin to patients with metastatic or recurrent carcinoma of the endometrium to evaluate its activity and to define its toxicity. Methods: Thirty-nine consecutive patients were treated on an outpatient basis with paclitaxel 150 mg/m2, administered intravenously over a 3-h period and followed by carboplatin at AUC of 5 on day 3, with both agents proceding topotecan that was given at 0.75 mg/m2/day on days 1 through 3. The chemotherapy was repeated every 3 weeks with granulocyte colony-stimulating factor (G-CSF) support for a maximum of six courses. Results: Twenty-one (60%) patients achieved objective clinical response (95% CI, 42.2-75.7%) including 4 (11.4%) complete and 17 (48.6%) partial responses. The median times to progression and survival for all patients were 8.9 and 17.7 months, respectively. Grade 3 or 4 thombocytopenia and neutropenia occurred in 5 (13%) and 4 (10%) patients, respectively, but only 2 episodes of neutropenic fever were encountered. Grade 2 or 3 neurotoxicity was observed in 23% of patients. Conclusions: The combination of paclitaxel, topotecan and carboplatin with G-CSF support appears active with acceptable toxicity in patients with metastatic or recurrent carcinoma of the endometrium. © 2008 Elsevier Inc.

Thalidomide with dexamethasone (thal-dex) is an active therapy for patients with relapsed or refractory multiple myeloma (MM). In this Practice Point, we discuss the findings of a trial by Rajkumar et al. that aimed to compare the response rate, time to progression and progression-free survival among previously untreated patients with MM who received either thal-dex or placebo plus dexamethasone. The thal-dex regimen was associated with a significantly higher response rate at the expense of more-frequent adverse effects, in particular deep-vein thrombosis, which occurred in almost 20% of patients. Median time to progression was three times longer with thal-dex than with placebo plus dexamethasone, but was shorter, however, than the time to progression observed in studies in which thalidomide or bortezomib was added to melphalan and prednisone. Nevertheless, thal-dex is a convenient oral and relatively inexpensive non-myelosuppressive regimen, which can be used in patients with previously untreated MM.

Patent WO02095012A1 claims for the development of antibodies against receptor activator of nuclear factor-κ B ligand (RANKL) and immunologically functional fragments that neutralize RANKL. These molecules can be used to detect RANKL in biological samples, allowing the identification of pathological conditions in which RANKL alteration contributes to their pathophysiology. The use of anti-RANKL antibodies is of high importance in the treatment of bone disorders characterized by the stimulation of osteoclast function and subsequent bone loss. Postmenopausal and steroid-induced osteoporosis, myeloma bone disease, cancer bone metastases with lytic lesions and bone loss due to rheumatoid disorders (including rheumatoid arthritis) are candidates for anti-RANKL therapy, as RANKL is implicated in their pathogenesis. © 2008 Informa UK Ltd.

This phase 2 study aimed to determine the efficacy and safety of the combination of bortezomib, melphalan, dexamethasone and intermittent thalidomide (VMDT) and its effect on bone remodeling and angiogenesis in relapsed/refractory myeloma. Bortezomib (1.0 mg/m2) was given on days 1, 4, 8, 11, oral melphalan (0.15 mg/kg) on days 1-4, whereas thalidomide (100mg per day) and dexamethasone (12 mg/m2) were administered on days 1-4 and 17-20 of a 28-day cycle, for four cycles. Patients without disease progression continued for up to eight cycles. VMDT effect on bone remodeling was evaluated by measuring osteoclast regulators (soluble receptor activator of nuclear factor-κ B ligand/osteoprotegerin ratio, osteopontin, macrophage inflammatory protein-1α), dickkopf-1 protein, bone resorption and formation markers, whereas its effect on angiogenesis was assessed by measuring serum vascular endothelial growth factor, angiogenin, angiopoietin-2 and basic fibroblast growth factor, after four cycles and at the study end. A total of 62 patients were enrolled. The overall response rate was 66%: CR 13%, vgPR 27% and PR 26%. Median time to response was 35 days and median time to progression was 9.3 months. Common adverse events included cytopenias, peripheral neuropathy and infections. No patient experienced deep-vein thrombosis. VMDT reduced angiogenic cytokines, osteoclast regulators, dickkopf-1 and bone resorption. We conclude that VMDT with intermittent thalidomide is an active and well-tolerated regimen for relapsed/refractory myeloma, affecting abnormal bone remodeling and angiogenesis.

The aim of the study was to evaluate the prognostic ability of the transcriptional profiling of the HER family genes in early breast cancer, as well as to investigate the predictive value of HER2 mRNA expression for adjuvant treatment with paclitaxel. RNA was extracted from 268 formalin-fixed paraffin-embedded (FFPE) tumour tissue samples of high-risk breast cancer patients enrolled in the randomised HE10/97 trial, evaluating the effect of dose-dense anthracycline-based sequential adjuvant chemotherapy with or without paclitaxel. The mRNA expression of all four HER family members was assessed by kinetic reverse transcription-polymerase chain reaction (kRT-PCR). The overall concordance between kRT-PCR and IHC/FISH for HER2 status determination was 74%. At a median follow-up of 8 years, multivariate analysis showed that EGFR and HER2 mRNA expression was associated with reduced overall survival (OS). HER3 and HER4 mRNA level had a favourable prognostic value in terms of OS and disease-free survival (DFS), respectively. Adjusting for HER2 mRNA expression, OS and DFS did not differ between treatment groups. These data indicate that EGFR as well as HER2 are prognostic factors of worse clinical outcomes, whereas HER3 and HER4 gene transcription is associated with better prognosis in high-risk early breast cancer. However, HER2 mRNA expression did not predict clinical benefit from paclitaxel. Kinetic RT-PCR represents an alternative method for evaluating the expression of HER family members in FFPE breast carcinomas. © 2008 Cancer Research.

Background: Giant cell arteritis (GCA) of the breast is one of the less recognized variants of this vasculitis and may represent an isolated finding or a manifestation of a more widespread disease. Case Report: We present the case of a 74-year-old woman with malaise and a 14-day persistent fever, reaching 38°C. There was a bilateral, painless and mobile axillary lymphadenopathy and a slight tenderness over the medial and lateral upper quadrants of her left breast, as well as an independent palpable tender mass in the upper outer quadrant of the same breast measuring 2 cm in its greatest diameter. Constitutional symptoms, anemia and an elevated erythrocyte sedimentation rate suggestive of polymyalgia rheumatica were also present. An invasive ductal carcinoma of the breast with coincidental pathologic findings of GCA in the same biopsy specimen was revealed. In this case, arteritis was limited to the breast and presented with diffuse breast tenderness. No other artery was involved by GCA. All arteritis-related symptoms disappeared after the removal of the tumor. Conclusions: There is a relationship between cancer, particularly breast cancer, and GCA of the same organ, but the real nature of this association still remains unknown. Copyright © 2008 S. Karger AG.

This analysis assessed the efficacy and safety of lenalidomide + dexamethasone in patients with relapsed or refractory multiple myeloma (MM) previously treated with thalidomide. Of 704 patients, 39% were thalidomide exposed. Thalidomide-exposed patients had more prior lines of therapy and longer duration of myeloma than thalidomide-naive patients. Lenalidomide + dexamethasone led to higher overall response rate (ORR), longer time to progression (TTP), and progression-free survival (PFS) versus placebo + dexamethasone despite prior thalidomide exposure. Among lenalidomide + dexamethasone-treated patients, ORR was higher in thalidomide-naive versus thalidomide-exposed patients (P = .04), with longer median TTP (P = .04) and PFS (P = .02). Likewise for dexamethasone alone-treated patients (P = .03 for ORR, P = .03 for TTP, P = .06 for PFS). Prior thalidomide did not affect survival in lenalidomide + dexamethasone-treated patients (36.1 vs 33.3 months, P > .05). Thalidomide-naive and thalidomide-exposed patients had similar toxicities. Lenalidomide + dexamethasone resulted in higher rates of venous thromboembolism, myelosuppression, and infections versus placebo + dexamethasone, independent of prior thalidomide exposure. Lenalidomide + dexamethasone was superior to placebo + dexamethasone, independent of prior thalidomide exposure. Although prior thalidomide may have contributed to inferior TTP and PFS compared with thalidomide-naive patients, these parameters remained superior compared with placebo + dexamethasone; similar benefits compared with placebo + dexamethasone were not evident for thalidomide-exposed patients in terms of overall survival. Studies were registered at http://www.clinicaltrials. gov under NCT00056160 and NCT00424047. © 2008 by The American Society of Hematology.

Purpose: To evaluate the natural history of bisphosphonate-related osteonecrosis of the jaw (ONJ) in patients with multiple myeloma. Patients and Methods: Ninety-seven patients with myeloma from the United States (n = 37) and Greece (n = 60) were observed prospectively for a minimum 3.2 years after ONJ. Patients characteristics were similar with regard to age, bisphosphonate use, and myeloma therapy, except more autologous transplantations were performed on patients in the United States than in Greece (73% v 28%; P < .0001). Results: ONJ resolved in 60 patients (62%), resolved and recurred in 12 patients (12%), and did not heal in 25 patients (26%). Dental procedures preceded ONJ in 46 patients (47%) and were more common in those with single episodes (35 of 60, 58%) than recurrent or nonhealing (11 of 37, 30%; P = .007). Recurrent ONJ followed reinitiation of bisphosphonates in six of 12 patients. Greek patients had more bone pain than United States patients (60% v 30%, P = .001) and were less likely to restart bisphosphonates (5% v 35%, P < .0002). Myeloma relapses were more common in patients with recurrent/nonhealing than single-episode ONJ (84% v 62%; P = .02). Median overall survival from myeloma diagnosis was 10.8 years (95% CI; 9.3 years to not reached) and did not differ between patients with single, recurrent, and nonhealing ONJ (P = .2). Conclusion: ONJ healed in 75% of patients. Patients with spontaneous ONJ have a higher risk of nonhealing and recurrence. Reinitiating bisphosphonates after healing of ONJ is a reasonable option in patients experiencing relapse who are at risk of skeletal complications. Further studies of the pathogenesis and healing of ONJ are needed. © 2008 by American Society of Clinical Oncology.

More than half of all serious adverse reactions are identified 7 or more years after a drug receives approval from the US Food and Drug Administration (FDA). In 2002, 9 months after the intravenous bisphosphonate zoledronic acid received regulatory approval for marketing, the FDA received reports of nine patients with cancer, who were treated with zoledronic acid, who unexpectedly developed osteonecrosis of the jaw. During the next 2 years, three oral surgeons described 104 patients with cancer with osteonecrosis of the jaw in the medical literature and identified intravenous bisphosphonate therapy as being common to the care of these patients. In subspecialty medical, radiology, and dental journals, case reports and case series described clinical features of osteonecrosis of the jaw in patients with cancer who were treated with bisphosphonates. Manufacturer-sponsored epidemiological studies reported the first estimates of the incidence of this toxic effect, ranging from 0·1% to 1·8%. By contrast, independent epidemiological efforts from clinicians and the International Myeloma Foundation reported incidence estimates between 5% and 10%. Between 2003 and 2005, warnings about the risks of bisphosphonate-associated osteonecrosis were disseminated by national regulatory agencies, the manufacturers of bisphosphonates, and the International Myeloma Foundation. From 2006, independent clinical recommendations for diagnosis, prevention, and treatment of this toxic effect have been disseminated by manufacturers, national regulatory authorities, the International Myeloma Foundation, and medical specialty organisations. Furthermore, independent efforts by pharmaceutical manufacturers, dental and medical professionals, a non-profit organisation (the International Myeloma Foundation), patients, and regulatory authorities has led to the rapid identification and dissemination of safety information for this serious adverse reaction. Better coordination of safety-related pharmacovigilance initiatives is now needed. © 2008 Elsevier Ltd. All rights reserved.

Kallikrein-related peptidases, a subgroup of the serine protease enzyme family, are considered important prognostic biomarkers in cancer. In the present study, we sought to determine the prognostic value of kallikrein-related peptidase 6 (KLK6) in ovarian cancer using a novel method of compartmentalized in situ protein analysis. A tissue array composed of 150 advanced stage ovarian cancers, uniformly treated with surgical debulking followed by platinum-paclitaxel combination chemotherapy, was constructed. For evaluation of KLK6 protein expression, we used an immunofluorescence-based method of automated in situ quantitative measurement of protein analysis (AQUA). Mean follow-up time of the cohort was 34.35 months. One hundred and thirty-five of 150 cases had sufficient tissue for AQUA analysis. In univariate survival analysis, low tumor KLK6 expression was associated with better outcome for overall survival over 3.years (P = 0.019). There was no association between tumor KLK6 expression and progression-free survival (P = 0.128). In multivariate survival analysis, adjusting for well-characterized prognostic variables, low tumor KLK6 expression level was one of the most significant predictor variable for overall survival (95% confidence interval, 1.19-3.50; P = 0.009). High tumor KLK6 protein expression is associated with inferior patient outcome in ovarian cancer. KLK6 may represent a promising disease biomarker and therapeutic target in ovarian cancer. © 2008 Japanese Cancer Association.

Background: Small cell carcinomas (SCC) originate mainly from bronchial tissue. Several extrapulmonary sites of origin have been described, including the genitourinary and gastrointestinal tracts, the ear, nose and throat and lymph nodes. SCC of the lung may be associated with paraneoplastic neurologic syndromes. Case Report: We report an oat cell histological variant of SCC found in the thymus gland of a 53-year-old woman who presented with subacute cerebellar dysfunction. Conclusions: SCC of the thymus gland, which is a rare extrapulmonary site of origin of SCC, accompanied by cerebellar dysfunction, is rarely reported.

Background: The prognostic significance of age in ovarian cancer has not been clarified. We investigated the characteristics of ovarian cancer presenting in ages >70 years and assessed the prognostic significance of advanced age. Patients and Methods: Four hundred and fifty-three patients with stage IIC-IV ovarian cancer (age>70 years n=106 [23%]), treated postoperatively with platinum-based chemotherapy were retrospectively reviewed. Results: Median overall survival (OS) of patients ≤70 years old (52.3 months, 95% CI: 43.2-61.3) was longer than that of older patients (38.8 months, 95% CI: 29.9-47.7) (p=0.005), but this difference was not significant in a multivariate analysis (p=0.978). Age >70 years was correlated with worse performance status (PS) (p=0.019), higher tumor grade (p=0.033), residual disease >2 cm (p=0.006) and less frequent paclitaxel administration (p<0.001). Toxicity from chemotherapy was similar between the two age groups, but the relative dose intensity of paclitaxel was lower among elderly patients. Conclusion: The worse outcome of ovarian cancer in elderly patients may be attributed to other associated adverse prognostic factors, but advanced age was not an independent prognostic factor.

BACKGROUND: The purpose of this study was to evaluate gemcitabine- carboplatin (GCb) versus single-agent gemcitabine (G) in patients with advanced non-small cell lung cancer (NSCLC) and a performance status (PS) of 2. The primary endpoint was clinical benefit. PATIENTS AND METHODS: Patients were randomly assigned to either 1250 mg/m of G (arm A) or 1250 mg/m of G plus carboplatin area under the curve of 3 (arm B). Both treatments were given on days 1 and 14 and were repeated every 28 days for up to four cycles. RESULTS: Among the 90 eligible patients (47 in arm A and 43 in arm B), in arm A, two (4%) had partial responses (95% CI, 0.52%-14.5%) and 10 (21%) had stable disease (95% CI, 10.7%-35.7%). In arm B, six (14%) had partial responses (95% CI, 5.3%-27.9%) and nine (21%) had stable disease (95% CI, 10%-36%) (p = 0.14). No significant difference was found in terms of clinical benefit between the two treatment groups after two cycles of treatment or at the end of chemotherapy. Furthermore, no association was found between clinical benefit and response to treatment (p > 0.05). Median survival was 4.8 months (95% CI, 2.45-7.25) for arm A and 6.7 months (95% CI, 2.47-10.8) for arm B (p = 0.49). Neutropenia (p = 0.007) and thrombocytopenia (p < 0.001) were more common in group B. Nevertheless, no significant differences were found in terms of severe toxicities (p > 0.05 in all cases). CONCLUSION: No significant difference was found in terms of clinical benefit in patients with NSCLC and PS 2 who received single-agent G or GCb. Nevertheless, GCb caused more toxicity, particularly neutropenia and thrombocytopenia. © 2007International Association for the Study of Lung Cancer.

Objectives.: Cervical cancer is a disease of middle-aged and elderly but still there are young women diagnosed with advanced disease that is incurable with local treatment and is treated with platinum-based combination chemotherapy. It is unknown whether these young patients have a poorer outcome compared to older patients or whether elderly patients have inferior outcome than younger patients when treated with combination chemotherapy. Methods.: We compared the outcome between young (< 35), elderly (> 70) and middle-aged (35-70) women who were treated with platinum-based combination chemotherapy for advanced, recurrent or persistent disease. Results.: Two hundred and eighteen patients were included in our database. The baseline clinical and disease characteristics were not different between age groups but anemia and thrombocytosis were more frequent in younger patients. Median survival for all patients was 13.4 (95%CI 11-15.8) months while survival of patients < 35 years of age was 9 months (95% CI 5.8-12), of patients older than 70 was 10 months (95% CI 6.9-13) of patients 35 to 70 years of age was 14.5 months (95% CI 11-18) (p = 0.004). Multiple factors were significant for survival in univariate analysis but only weight loss, pain score and relapse inside an irradiated filed were significant predictors of outcome in multivariate analysis. Conclusions.: Very young (< 35) and elderly (> 70) patients have a worse prognosis after treatment with combination chemotherapy for advanced or recurrent cervical cancer. Nevertheless, this difference is not significant when adjusted for other prognostic factors. © 2006 Elsevier Inc. All rights reserved.

Study objective: To assess whether laparoscopy is a reliable technique for the investigation of women presenting with ascites and in whom the diagnosis remains obscure. Design: Prospective nonrandomized clinical study (Canadian Task Force classification II-2). Setting: University Departments of a tertiary referral center. Patients: Women presenting in our institution with ascites in whom the diagnosis remained obscure after an extensive nonoperative diagnostic work-up. Intervention: Undiagnosed cases were submitted to laparoscopy, and selective biopsy specimens were taken for histologic study. Measurements and main results: Over a 3-year period, 73 patients were admitted to our institution with diffuse ascites. In 9 patients (12.3%), the diagnosis remained obscure, and these patients were further investigated with laparoscopy. Selective biopsy specimens obtained at laparoscopy clarified the specific cause of the ascites in all 9 patients. Peritoneal carcinomatosis was responsible in 5 patients (a metastatic gastrointestinal tumor in 1 patient, a malignant mesothelioma of the peritoneum in 1 patient, and a serous papillary carcinoma of the peritoneum and of the ovary in 2 and 1 patients, respectively). Three patients were found with miliary peritoneal tuberculosis, and the last patient had an unusual peritoneal reaction to methylene blue after laparoscopic adhesiolysis. Conclusion: Laparoscopy is a valuable means of assessing the peritoneal cavity in patients with unexplained ascites, where the primary cause remains unclear. The diagnosis can be accurately made with selective biopsy specimens, and appropriate treatment can be instituted without delay. © 2007 AAGL.

Renal failure (RF) is a common and severe complication of patients with multiple myeloma (MM). The purpose of our study was to assess the incidence of RF in a contemporary series of newly diagnosed patients with MM, its association with specific clinical and laboratory features, and its impact on patients' outcome. Over the last decade, 756 newly diagnosed symptomatic patients with MM were included in our database. Renal failure, defined as a serum creatinine ≥mg/dl at the time of diagnosis, was seen in 21% of patients. Multiple parameters were associated with RF, but logistic regression analysis showed that RF was independently associated only with International Staging System and Bence Jones proteinuria. The presence of RF was associated with a trend for higher early death rate but with a similar response to primary therapy. The median survival of patients with RF was 19.5 months versus 40.4 months for patients without RF (p < 0.001). Several variables were associated with impaired survival by univariate analysis. When multivariate analysis was performed the independent variables were poor performance status, thrombocytopenia, advanced age, high LDH and elevated serum β2 microglobulin but not high creatinine. When corrected for stage, renal failure had no impact on survival.

The role of receptor activator of nuclear factor-κB ligand (RANKL)/osteoprotegerin (OPG) system, and osteopontin (OPN) was studied in patients with solid tumors metastatic to the bone in relation to the type of malignancy and the neoplastic burden to the skeleton. Levels of soluble RANKL (sRANKL), OPG and OPN were assessed in 61 patients with breast, lung and prostate cancer with newly-diagnosed metastasis to the bone, in parallel with bone resorption [C-telopeptide of type-I collagen (CTX), tartrate-resistant acid phosphatase-5b (TRACP-5b)] and bone formation markers [bone-alkaline phosphatase (bALP), osteocalcin (OC), and C-terminal propeptide of collagen type-I (CICP)]. Patients had elevated serum levels of sRANKL, OPG, OPN, TRACP-5b, and bALP, and reduced OC levels compared to controls. OPG correlated with the extent of metastatic bone burden. Patients with breast and lung cancer shared increased levels of sRANKL, OPG, and OPN whereas prostate cancer patients had elevated values of OPG and bALP only. These results suggest that patients with solid tumors metastatic to the bone have severe disruption of the sRANKL/OPG axis. Breast and lung cancer seem to exert their osteolytic action through upregulation of the sRANKL/OPG system and OPN, whereas prostate cancer seems to provoke profound elevation of OPG levels only, thus leading to increased osteoblastic activity. © 2007 Taylor & Francis.

Background: p53 protein is regarded as a valuable prognostic marker in cancer with a potential use as a molecular target. Here, we sought to determine the prognostic value of p53 in ovarian cancer using a novel method of compartmentalized in situ protein analysis. Patients and methods: A tissue array composed of 141 advanced stage ovarian cancers uniformly treated was constructed. For evaluation of p53 protein expression, we used an immunofluorescence-based method of automated in situ quantitative measurement of protein analysis (AQUA). Results: High nuclear p53 expression levels were associated with better outcome for overall survival (OS) (P = 0.0023) and disease-free survival (P = 0.0338) at 5-years. High cytoplasmic p53 expression levels were associated with better outcome for OS (P = 0.0002). In multivariable analysis, high nuclear and high cytoplasmic p53 level with International Federation of Gynecology and Obstetrics (FIGO) stage were the most significant predictor variables for OS and high nuclear p53 level with FIGO stage were the significant predictor variables for disease-free survival. Conclusions: Assessment of the prognostic value of p53 protein levels using conventional immunohistochemistry is limited by the nonquantitative nature of the method. AQUA provides precise estimation of p53 protein levels and was able to elucidate the association of p53 protein levels and ovarian cancer prognosis. © 2007 Oxford University Press.

Purpose of investigation: Uterine sarcomas are rare neoplasms characterized by a high rate of local recurrences and distant metastases. The role of chemotherapy in early-stage completely resected disease remains controversial. Methods: Thirty-one patients with Stage I or II uterine sarcomas, referred to our center for adjuvant chemotherapy, received anthracycline-based regimens. Seventeen (54.8%) patients received ifosfamide, etoposide and epirubicin, six (19.4%) were treated with doxorubicin and carboplatin, three (9.6%) were administered doxorubicin and ifosfamide, while five (16.1%) patients received various anthracycline-based regimens. Results: With a median follow-up of 82 months disease recurred in 12 (38.7%) patients. Five-year survival probability is estimated at 54%. Both median overall survival and time to progression for all patients have not been reached yet. Patients who received ifosfamide-containing regimens had a statistically significant benefit in overall survival (p ≤ 0.05) when compared with those treated with non-ifosfamide-containing regimens. Conclusion: Our data suggest a potential role for anthracycline- and ifosfamide-containing chemotherapy in the adjuvant setting for early-stage uterine sarcomas.

Objectives: Synergism between gemcitabine and cisplatin is supported by preclinical and clinical data. The present study explores the efficacy of a biweekly regimen in platinum-resistant/refractory, paclitaxel-pretreated ovarian and peritoneal cancer. Methods: 50 paclitaxel-pretreated patients with platinum-resistant/refractory ovarian or peritoneal carcinoma who had previously received paclitaxel chemotherapy, were treated with six cycles of gemcitabine 1000 mg/m2 followed by cisplatin 40 mg/m2 on days 1 and 15, repeated every 4 weeks. Results: The median platinum-free interval (PFI) was 4 months while the median number of previous treatment lines was 2. Chemotherapy was well tolerated. Objective responses were observed in 31.5% of evaluable patients (n = 35). CA125 response was observed in 68% of patients with elevated CA125 (n = 41). Median overall survival (OS) was 13.2 months (95% Confidence Interval, CI: 10.2-16.2) while progression-free survival (PFS) was 4.9 months (95%CI: 3.5-6.4). A PFI of less than 3 months was associated with lower objective response rates (15.8% versus 50%, p = 0.03). Conclusions: Biweekly gemcitabine and cisplatin is feasible for patients with platinum-resistant ovarian or peritoneal cancer and is associated with a favorable toxicity profile. In a population with recent exposure to platinum, a PFI of less than 3 months was the major factor influencing response to chemotherapy. © 2007 Elsevier Inc. All rights reserved.

Lenalidomide is an immunomodulatory drug, structurally related to thalidomide, which has pleotropic activity, including antiangiogenic and antineoplastic properties. This agent is the product of advances in the understanding of the biology of neoplastic cells, their interaction with the microenvironment and of the underlying molecular pathways. Lenalidomide has shown significant activity in refractory/resistant multiple myeloma, and further studies have shown its activity in other hematologic malignancies with some very encouraging results, especially in subsets of patients with myelodysplastic syndromes. This article reviews the data on lenalidomide use in patients with multiple myeloma, as well as in myelodysplastic syndromes, chronic lymphocytic leukemia and myelofibrosis with myeloid metaplasia. © 2007 Informa UK Ltd.

There are limited data regarding the long term follow up after thalidomide based regimen and the outcome of patients when they progress and they receive further treatment. We reassessed our original series of 43 patients with previously treated multiple myeloma who had received a pulsed cyclophosphamide, thalidomide, dexamethasone (CTD) regimen. Among the 43 patients, 14 did not respond to pulsed CTD and 29 (67%) achieved at least a partial response. The median PFS for all patients was 10 months. After a median follow up of 24 months (range 1-62), the 3 year PFS is 14% and 3 patients remain off treatment and without progression for 55+, 55+ and 56+ months respectively. Moreover, 28% of patients who progressed after CTD achieved a partial response after subsequent treatment which included thalidomide, bortezomib or lenalidomide. The median PFS of these patients was 5 months and the 1 year PFS was 20%. Furthermore, 31% of patients who had responded to CTD and then progressed (CTD sensitive) responded to subsequent treatment. We conclude that some patients enjoy long responses after CTD and that several patients who progress after CTD may respond to treatment with a novel agent-based regimen.

The impact of high dose dexamethasone containing regimens with or without the novel agents thalidomide and bortezomib on the reversal of renal failure (RF) was evaluated in 41 consecutive newly diagnosed patients with multiple myeloma (MM) treated in a single institution. RF was reversed in 73% of all patients within a median of 1.9 months. In patients treated with dexamethasone and novel agents (thalidomide and/or bortezomib) the reversibility rate was 80% within a median of 0.8 months. Severe RF and significant Bence Jones proteinuria were associated with a lower probability of RF reversal. Patients who responded to treatment achieved RF reversal more often than in those who did not (85% versus 56%, p=0.046). In conclusion, RF is reversible in the majority of newly diagnosed MM patients treated with high-dose dexamethasone containing regimens. The addition of novel agents induces a more rapid RF reversal. ©2007 Ferrata Storti Foundation.

Angiogenesis represents an essential step of disease progression in several haematological malignancies. Microvessel density is increased in 30% of patients with Waldenstrom macroglobulinaemia (WM), but there is very limited information regarding the role of angiogenic cytokines in this disease. Serum levels of vascular endothelial growth factor (VEGF), VEGF-A, angiogenin, angiopoietin (Ang)-1 and -2, and basic fibroblast growth factor (bFGF) were evaluated in 56 WM patients at different disease phases (24 untreated, 20 relapsed/refractory and 12 patients at remission) and 11 patients with immunoglobulin M type monoclonal gammopathy of undetermined significance (IgM-MGUS). All patients had increased levels of angiogenin, VEGF, VEGF-A, and bFGF compared with controls. The Ang-1/Ang-2 ratio was reduced in WM but not in IgM-MGUS patients. Angiogenin levels correlated with disease status: when compared with healthy subjects, patients with IgM-MGUS and untreated WM patients had increased angiogenin serum levels, which were higher in untreated WM patients than in MGUS. WM patients at remission had lower angiogenin serum levels compared with untreated patients, but these levels were increased again in active disease post-therapy. Angiogenin also correlated with albumin levels, while VEGF-A correlated with β2-microglobulin (β2M). Ang-1/Ang-2 ratio showed a strong, negative correlation with β2M, and positive correlation with albumin, haemoglobin and lymphadenopathy. Our results indicate a potential use of angiogenin levels for follow-up in WM and angiogenic molecules as targets for the development of novel anti-WM agents. © 2007 The Authors.

Waldenstrom's macroglobulinemia is defined by bone marrow lymphoplasmacytic infiltration and by production of monoclonal IgM. Treatment is employed only to symptomatic patients. Alkylating agents (chlorambucil), nucleoside analogues and rituximab are reasonable choices for primary therapy. Combination therapy either with nucleoside analogues with alkylating agents and/or rituximab or rituximab with chemotherapy such as CHOP or cyclophosphamide are also reasonable frontline treatment options for WM patients. Several factors should be taken into account when choosing the most appropriate primary treatment. These factors include the age of the patient and possible co-morbidities, the presence of cytopenias and especially thrombocytopenia, the presence of symptoms and signs indicative of hyperviscosity, the need for rapid disease control due to severe symptoms, significant splenomegaly or lymphadenopathy, symptomatic peripheral neuropathy and whether the patient is candidate for autologous stem cell transplantation. For patients with refractory or relapsing disease, the use of an alternate first-line agent is reasonable. Outside the setting of a clinical trial, the administration of high-dose therapy should be reserved only for patients refractory to alkylating agents, purine nucleoside and rituximab. For patients who develop resistance to all three classes of agents, alemtuzumab, thalidomide with or without dexamethasone or bortezomib could be tried. © Springer Science+Business Media, LLC 2007.

Background: In this study we investigated whether administering CEOP (cyclophosphamide, epirubicin, vincristine [Oncovin], and prednisone) every 2 weeks (CEOP-14) instead of every 3 weeks (the standard CEOP-21 regimen) improves outcomes in patients with previously untreated aggressive lymphomas. In a secondary analysis we evaluated the impact of adding rituximab to CEOP-14/CEOP-21 chemotherapy. Study Design: The trial opened in March 1999, and patients were randomly assigned to either CEOP-14 or CEOP-21. All patients enrolled from May 2002 onward received rituximab with each chemotherapy cycle, and those attaining a complete response received rituximab consolidation. Results: Complete and overall response rates in the CEOP-21 ± rituximab (N ≤ 114) and CEOP-14 ± rituximab (N ≤ 103) arms were similar, as were the overall survival (P ≤ 0.769) and time to progression distributions (P ≤ 0.969). Rituximab was shown to have a beneficial effect both on the overall survival and on the time to progression. Conclusions: Thus far, no significant improvement in outcome has been demonstrated with CEOP-14 ± rituximab versus CEOP-21 ± rituximab. However, with addition of rituximab to CEOP-21/CEOP-14, significant improvements in time to progression and overall survival were achieved. © 2007 by Lippincott Williams & Wilkins.

Concurrent chemoradiotherapy has become a standard therapy for locoregionally advanced inoperable non-small cell lung cancer (NSCLC). The purpose of this phase II trial was to evaluate the efficacy and toxicity of concurrent chemoradiotherapy following induction with non-platinum chemotherapy in patients with inoperable locally advanced NSCLC. Patients and Methods: All patients with locally advanced inoperable NSCLC ECOG performance status (PS): 0-1 following staging received paclitaxel 200 mg/m2 in a 3-h infusion on day 1 and gemcitabine 1000 mg/m2 on days 1 and 8 every 21 days for two cycles. The patients with a response or stable disease (SD) continued to receive paclitaxel 60 mg/m2 weekly and radiotherapy 63 Gy given at 1.8 Gy once a day for 7 weeks. Results: Forty-three eligible patients entered the study. The median age was 63 years (range 42-76), male 93%, IIIB 63% and IIIA 37%. Following induction 15 (36.5%) of the patients responded: complete response (CR), 2%; partial response (PR), 33%; and 19 (46.5%) SD. From those with SD, 7 (37%) improved to a PR following concurrent chemoradiotherapy. With a median follow-up of 44 months (95% CI: range 36-53) the median survival was 20.8 months (95%c CI: range 15.4-26.3) and time-to-progression 8.4 months (95% CI: range 6.2-10.6). The median survival of those who had improved response from SD to PR was 31.4 months (95% CI: range 18.7-44.1) versus 20.8 months (95% CI: range 5.5-11.3) for those who had no improvement (p=0.20). The commonest grade 3/4 toxicity in induction was neutropenia 12% with 2 febrile neutropenic patients whereas in the concurrent chemoradiotherapy neutropenia, neurotoxicity and oesophagitis were observed in 6% of the patients. Conclusion: Concurrent chemoradiotherapy following induction chemotherapy in patients with stage III NSCLC is feasible with reasonable efficacy and acceptable toxicity.

Immunomodulatory drugs (IMiDs) and bortezomib have been recently used in the management of patients with both newly diagnosed and relapsed/ refractory multiple myeloma. Except of their direct anti-myeloma effect, these agents also alter the interactions between myeloma cells and marrow microenvironment. Several recent studies have investigated their potential effect on myeloma bone disease. Preclinical studies have demonstrated that IMiDs reduce osteoclast formation and function in vitro. Clinical studies have confirmed that thalidomide reduces markers of bone resorption, while lenalidomide induces osteoclast arrest in myeloma patients. However, IMiDs seem to have no effect on osteoblast exhaustion present in myeloma. The proteasome inhibitor bortezomib restores abnormal bone remodeling through the inhibition of osteoclast function and the increase in osteoblast differentiation and activity in vitro. In myeloma patients, bortezomib reduces biochemical markers of bone resorption and normalizes the RANKL/osteoprotegerin ratio, while at the same time increases bone formation markers reducing levels of dickkopf-1 protein. Whether these effects are direct and not only a consequence of the agents' antimyeloma activity is not totally clear. This review summarizes all available data for these attractive agents that combine potent anti-myeloma activity with beneficial effects on bone and may alter the way of management of myeloma-related bone disease.

We retrospectively investigated the outcome of epithelial ovarian cancer (EOC) in women less than 45 years and over 70 years treated with cisplatin-based chemotherapy. We also investigated the impact of various factors on patients' survival. The tumor registry of the Hellenic Cooperative Oncology Group was used to identify women less than 45 years and over 70 years with EOC diagnosed between 1979 and 2004. Survival was calculated by the Kaplan-Meier method, and Cox proportional hazard models were used to determine the independent effect of each variable on survival. Of 1748 EOC patients, 200 were 45 or younger and 282 were over 70 years old. In the univariate analysis, younger age (P < 0.001), better performance status (PS) (P < 0.001), early stage (P < 0.001), 0-2 cm residual disease (P < 0.001), and well or moderate differentiation grade (P = 0.004) were significant prognostic factors for improved survival. In the multivariate analysis, older age (hazard ratio [HR]: 1.88, 95% CI: 1.27-2.77, P = 0.002), advanced stage (HR: 2.87, 95% CI: 1.49-5.52, P = 0.002), PS >1 (HR: 1.91, 95% CI: 1.18-3.08, P = 0.008), and residual disease (HR: 1.46, 95% CI: 1.01-2.13, P = 0.046) were independently associated with inferior survival. With a median follow-up of 45 months (range 0.1-197 months), median survival (118.5 months) of younger patients differed significantly compared to that of older patients (33 months) (P < 0.001). In conclusion, younger women with EOC have significantly improved survival compared to older patients. Age, PS, stage of the disease at diagnosis, and residual disease are important independent predictors for survival. © 2007, IGCS and ESGO.

Minichromosome maintenance proteins (MCM) have recently emerged as novel proliferation markers with prognostic implications in several tumour types. This is the first study investigating MCM-2 and MCM-5 immunohistochemical expression in a series of ovarian adenocarcinomas and low malignant potential (LMP) tumours aiming to determine possible associations with clinicopathological parameters, the conventional proliferation index Ki-67, cell cycle regulators (p53, p27Kip1, p21WAF1 and pRb) and patients' outcome. Immunohistochemistry was applied in a series of 43 cases of ovarian LMP tumours and 85 cases of adenocarcinomas. Survival analysis was restricted to adenocarcinomas. The median MCM-2 and MCM-5 labelling indices (LIs) were significantly higher in adenocarcinomas compared to LMP tumours (P<0.0001 for both associations). In adenocarcinomas, the levels of MCM-2 and MCM-5 increased significantly with advancing tumour stage (P=0.0052 and P=0.0180, respectively), whereas both MCM-2 and MCM-5 increased significantly with increasing tumour grade (P=0.0002 and P=0.0006, respectively) and the presence of bulky residual disease (P<0.0001 in both relationships). A strong positive correlation was established between MCM-2 or MCM-5 expression level and Ki-67 LI (P<0.0001) as well as p53 protein (P=0.0038 and P=0.0500, respectively). Moreover, MCM-2 LI was inversely correlated with p27Kip-1 LI (P=0.0068). Finally, both MCM-2 and MCM-5 were associated significantly with adverse patients' outcome in both univariate (≥20 vs >20%, P=0.0011 and ≥25 vs <25%, P=0.0100, respectively) and multivariate (P=0.0001 and 0.0090, respectively) analysis. An adequately powered independent group of 45 patients was used in order to validate our results in univariate survival analysis. In this group, MCM-2 and MCM-5 expression retained their prognostic significance (P<0.0001 in both relationships). In conclusion, MCM-2 and MCM-5 proteins appear to be promising as prognostic markers in patients with ovarian adenocarcinomas. © 2007 Cancer Research UK.

Bone disease is one of the most debilitating manifestations of multiple myeloma. A complex interdependence exists between myeloma bone disease and tumor growth, creating a vicious circle of extensive bone destruction and myeloma progression. Proteasome inhibitors have recently been shown to promote bone formation in vitro and in vivo. Preclinical studies have demonstrated that proteasome inhibitors, including bortezomib, which is the first-in-class such agent, stimulate osteoblast differentiation while inhibiting osteoclast formation and bone resorption. Clinical studies are confirming these observations. Bortezomib counteracts the abnormal balance of osteoclast regulators (receptor activator of nuclear factor-κB ligand and osteoprotegerin), leading to osteoclast inhibition and decreased bone destruction, as measured by a reduction in markers of bone resorption. In addition, bortezomib stimulates osteoblast function, possibly through the reduction of dickkopf-1, leading to increased bone formation, as indicated by the elevation in bone-specific alkaline phosphatase and osteocalcin. The effect of bortezomib on bone disease is thought to be direct and not only a consequence of the agent's antimyeloma properties, making it an attractive agent for further investigation, as it may combine potent antimyeloma activity with beneficial effects on bone. However, the clinical implication of these effects requires prospective studies with specific clinical end points. © 2007 by The American Society of Hematology.

Purpose: Alkylating agents and the anti-CD20 monoclonal antibody rituximab are among appropriate choices for the primary treatment of symptomatic patients with Waldenström macroglobulinemia (WM), and they induce at least a partial response in 30% to 50% of patients. To improve these results, we designed a phase II study that included previously untreated symptomatic patients with WM who received a combination of dexamethasone, rituximab, and cyclophosphamide (DRC). Patients and Methods: Seventy-two patients were treated with dexamethasone 20 mg intravenously followed by rituximab 375 mg/m2 intravenously on day 1 and cyclophosphamide 100 mg/m2 orally bid on days 1 to 5 (total dose, 1,000 mg/m2). This regimen was repeated every 21 days for 6 months. Patients' median age was 69 years and many had features of advanced disease such as anemia (57%), hypoalbuminemia (40%), and elevated serum beta2-microglobulin (43%). Results: On an intent-to-treat basis, 83% of patients (95% CI, 73% to 91 %) achieved a response, including 7% complete, 67% partial, and 9% minor responses. The median time to response was 4.1 months. The 2-year progression-free survival rate for all patients was 67%; for patients who responded to DRC, it was 80%. The 2-year disease-specific survival rate was 90%. Treatment with DRC was well tolerated, with 9% of patients experiencing grade 3 or 4 neutropenia and approximately 20% of patients experiencing some form of toxicity related to rituximab. Conclusion: Our large, multicenter trial showed that the non-stem-cell toxic DRC regimen is an active, well-tolerated treatment for symptomatic patients with WM. © 2007 by American Society of Clinical Oncology.

Objectives: Tumor infiltrating lymphocytes (TILs) and T regulatory cells (Tregs) have been associated with prognosis in ovarian cancer, but their prognostic significance in ascites has not been studied. We performed a prospective study of T lymphocytes isolated from ascites from patients with ovarian carcinoma and we compared them with the respective populations in blood and tumors. Methods: Mononuclear cells from ascites (n = 71) and blood were isolated by Ficoll, while tumor lymphocytes (n = 20) were obtained upon mechanical dissociation. Phenotypic analysis was performed with flow cytometry. Ascites from 10 patients with cirrhosis was used as control. Results: Tregs containing CD4+CD25+ cells, NK-T containing CD3+CD56+ cells and CD69 and HLADR expression of CD4 and CD8 lymphocytes were significantly increased in tumor ascites compared to blood and control ascites. A selective accumulation of these populations in the ascites of cancer patients, was suggested by the significantly higher ascites/blood (A/B) ratios in cancer patients but not controls. Cancer cell content in ascites was correlated with CD4+CD25+, CD4+CD69+, CD4+HLADR+ and CD8+CD69+ cells. There was no correlation of lymphocyte populations between ascites and samples from peritoneal metastases. Higher tumor grade was associated with increased A/B CD4+CD25+ ratio and reduced CD3+CD56+ cells, while platinum resistance was associated with reduced A/B CD3+CD56+ ratio. Conclusions: There are significant differences of CD3+CD56+ and CD25+CD4+ lymphocytes and increase in lymphocyte activation between blood, ascites and peritoneal metastases from patients with ovarian cancer. The selective accumulation of CD3+CD56+ population in ascites may be a predictive factor for platinum resistance. © 2007 Elsevier Inc. All rights reserved.

Background and Objectives: High-dose melphalan and autologous stem cell transplantation is currently the treatment of choice for selected patients with AL amyloidosis; however, new treatments are needed for patients who are ineligible for or relapse after this procedure. Bortezomib is a proteasome inhibitor with proven activity in multiple myeloma, and the addition of dexamethasone results in superior outcome. We evaluated the activity and feasibility of the combination of bortezomib and dexamethasone (BD) in patients with AL amyloidosis. Design and Methods: Consecutive patients with histologically proven, symptomatic AL amyloidosis were treated with BD. Results: Eighteen patients, including seven who had relapsed or progressed after previous therapies were treated with BD. Eleven (61%) patients had two or more organs involved; kidneys and heart were affected in 14 and 15 patients, respectively. The majority of patients had impaired performance status and high brain natriuretic peptide values; serum creatinine was elevated in six patients. Among evaluable patients, 94% had a hematologic response and 44% a hematologic complete response, including all five patients who had not responded to prior high dose dexamethasone-based treatment and one patient under dialysis. Five patients (28%) had a response in at least one affected organ. Hematologic responses were rapid (median 0.9 months) and median time to organ response was 4 months. Neurotoxicity, fatigue, peripheral edema, constipation and exacerbation of postural hypotension were manageable although necessitated dose adjustment or treatment discontinuation in 11 patients. Interpretation and Conclusions: The combination of BD is feasible in patients with AL amyloidosis. Patients achieve a rapid hematologic response and toxicity can be managed with close follow-up and appropriate dose adjustment. This treatment may be a valid option for patients with severe heart or kidney impairment. ©2007 Ferrata Storti Foundation.

Background: We have previously demonstrated that vincristine, liposomal doxorubicin and dexamethasone (VAD-doxil) is equally effective with VAD-bolus yielding objective response rates of 61% as first-line treatment in multiple myeloma (MM). In a phase II study, the addition of thalidomide to VAD-doxil (TVAD-doxil) proved feasible and increased response rate to 74%. The aim of the present multicenter prospective randomized clinical trial was to compare the efficacy and toxicity of VAD-doxil and TVAD-doxil in previously untreated MM patients. Patients and methods: We enrolled 232 newly diagnosed MM patients aged <75 years, 115 randomized to VAD-doxil (arm A) and 117 to TVAD-doxil (arm B). Patients in arm A received vincristine 2 mg i.v. and liposomal doxorubicin 40 mg/m2 i.v., on day 1 and dexamethasone 40 mg p.o. daily on days 1-4, 9-12 and 17-20 for the first cycle and on days 1-4 for the next three cycles. Patients in arm B received additionally thalidomide 200 mg p.o. daily, at bedtime. Treatment was administered every 28 days. Results: On an intention-to-treat basis, at least partial response was observed, in 62.6% and in 81.2% of patients randomized to arms A and B, respectively (P = 0.003). Progression-free survival (PFS) at 2 years was 44.8% in arm A and 58.9% in arm B (P = 0.013). Overall survival (OS) at 2 years was 64.6% and 77%, in arms A and B, respectively (P = 0.037). Considering overall toxicity, constipation, peripheral neuropathy, dizziness/somnolence, skin rash and edema were significantly higher in arm B compared with arm A (P < 0.01), but grade 3-4 toxicities were low and similar in both arms. Conclusions: The addition of thalidomide to VAD-doxil increases response and PFS rates and probably OS in previously untreated myeloma patients. The superiority of efficacy counterbalances the higher overall toxicity of TVAD-doxil. © 2007 European Society for Medical Oncology.

Objective: The purpose of this study was to evaluate the efficacy and toxicity of cisplatin, etoposide and irinotecan as first-line treatment in patients with extensive small-cell lung cancer (E-SCLC). Patients and methods: Chemo-naïve adult patients with a performance status (PS) of 0-2 and adequate organ function were eligible. Patients received cisplatin 20 mg/m2 i.v. daily for three consecutive days, etoposide 75 mg/m2 i.v. daily for three consecutive days and irinotecan 120 mg/m2 i.v. on day 2, every 21 days for six to eight cycles. Administration of G-CSF was given in the presence of febrile neutropenia and as a 5-day prophylaxis around the recorded nadir day in patients who developed grades 3-4 neutropenia. Results: Fifty-six patients were assessable. The median age was 62.2 years; 96.4% had PS 0-1, 33.5% had >3 metastatic sites. The overall response rate was 80.4% with 8 (14.3%) patients achieving a complete response. The median time to tumor progression was 7.8 months [95% confidence interval (CI), 7.1-8.6 months] with a median survival of 15.1 months [95% CI, 9.7-20.5 months] and 1-year survival rate of 56.5%. One patient died from toxicity. Grades 3-4 neutropenia occurred in 37.5% of patients, grades 3-4 thrombocytopenia occurred in 10.9% of patients and 11 (19.6%) patients developed febrile neutropenia. Grades 3-4 non-hematological toxicities were primarily nausea-vomiting 3.6%, diarrhea 7.1% and fatigue 3.6%. Conclusion: This study strongly suggests that cisplatin, etoposide and irinotecan combination is very effective for the treatment of E-SCLC with good safety profile. The triplet regimen currently seems a promising regimen and has to be further explored in phase III trials. © 2007 Elsevier Ireland Ltd. All rights reserved.

Background: Lenalidomide is a structural analogue of thalidomide with similar but more potent biologic activity. This phase 3, placebo-controlled trial investigated the efficacy of lenalidomide plus dexamethasone in the treatment of relapsed or refractory multiple myeloma. Methods: Of 351 patients who had received at least one previous antimyeloma therapy, 176 were randomly assigned to receive 25 mg of oral lenalidomide and 175 to receive placebo on days 1 to 21 of a 28-day cycle. In addition, all patients received 40 mg of oral dexamethasone on days 1 to 4, 9 to 12, and 17 to 20 for the first four cycles and subsequently, after the fourth cycle, only on days 1 to 4. Patients continued in the study until the occurrence of disease progression or unacceptable toxic effects. The primary end point was time to progression. Results: The time to progression was significantly longer in the patients who received lenalidomide plus dexamethasone (lenalidomide group) than in those who received placebo plus dexamethasone (placebo group) (median, 11.3 months vs. 4.7 months; P<0.001). A complete or partial response occurred in 106 patients in the lenalidomide group (60.2%) and in 42 patients in the placebo group (24.0%, P<0.001), with a complete response in 15.9% and 3.4% of patients, respectively (P<0.001). Overall survival was significantly improved in the lenalidomide group (hazard ratio for death, 0.66; P = 0.03). Grade 3 or 4 adverse events that occurred in more than 10% of patients in the lenalidomide group were neutropenia (29.5%, vs. 2.3% in the placebo group), thrombocytopenia (11.4% vs. 5.7%), and venous thromboembolism (11.4% vs. 4.6%). Conclusions: Lenalidomide plus dexamethasone is more effective than high-dose dexamethasone alone in relapsed or refractory multiple myeloma. (ClinicalTrials.gov number, NCT00424047.) Copyright © 2007 Massachusetts Medical Society.

Studies of bortezomib, thalidomide, and lenalidomide have shown promising clinical activity in relapsed/refractory multiple myeloma (MM). Bortezomib alone and in combination with other agents is associated with high response rates, consistently high rates of complete response, and a predictable and manageable profile of adverse events. Thalidomide-based regimens have also shown substantial clinical activity. The accumulating experience from ongoing trials of bortezomib/lenalidomide/dexamethasone combinations in patients who have relapsed/refractory or newly diagnosed MM will provide critical information that will determine the possible role of this combination as the basic backbone for combination regimens for management of advanced MM. © 2007 Elsevier Inc. All rights reserved.

Background and Objectives: As new therapeutic options for multiple myeloma (MM) emerge, identification of biological markers which could predict clinical response to standard treatment with high-dose melphalan (HDM) supported by autologous stem cell transplantation (ASCT) becomes more important. Design and Methods: Melphalan-induced damage formation and repair of monoadducts and interstrand cross-links in the p53 gene were studied in peripheral blood mononuclear cells obtained from 32 patients prior to therapy. The same studies were performed in the peripheral blood cells of these patients immediately after subsequent HDM administration. Clinical response and time to progression were correlated with molecular end-points obtained in vitro. Results: Values for all molecular end-points examined in vitro were highly correlated with the respective in vivo results within individual patients. All in vitro end-points indicative of increased DNA damage and slower repair capacity were predictive of a favorable response to HDM; the area under the curve of total adducts (AUC-TA) had the highest predictive ability. Using the cut-off value of 736 adducts/106 nucleotides x h for the AUC-TA, the positive predictive value for clinical response to HDM was 100%. Moreover, patients with an AUC-TA equal to or higher than this cut-off value had significantly longer times to progression than had patients with an AUC-TA lower than the cut-off value (hazard ratio 0.19; 95% confidence intervals 0.06 to 0.60). Interpretation and Conclusions: An in vitro assay to quantify melphalan-induced p53-specific damage formation/repair can be used to select those patients with MM who are more likely to benefit from HDM supported by ASCT. ©2007 Ferrata Storti Foundation.

Thalidomide - either alone or in combination with dexamethasone or chemotherapy - has shown significant activity in relapsed/refractory disease. When used in the induction regimens in untreated patients, it significantly increases the response rates as well progression-free survival. Moreover, thalidomide as a maintenance therapy has become a very attractive option. However, the toxicity profile of the drug, mainly neurotoxicity and thrombotic events, mandate careful monitoring of patients treated with thalidomide, whether as the first line, in the relapsed setting, or as maintenance. In this chapter we will review the pharmacology, mechanisms of action, and toxicity of the drug, and will focus on available data from clinical experience and randomized trials of thalidomide in the different settings of multiple myeloma: refractory/relapsed disease, upfront treatment in patients who are eligible for high-dose therapy as well as those who are not, and finally the use of thalidomide as a maintenance treatment. © 2007 Elsevier Ltd. All rights reserved.

Objectives: Adjuvant carboplatin is used as adjuvant therapy in Stage I testicular seminoma. Although cure is the rule, relapses still occur, especially in high-risk populations. We report the results of a risk-adapted strategy by the Hellenic Cooperative Oncology Group. Methods: From 1996 to 2003, 64 patients with Stage I seminoma and one of two risk factors (maximal tumor diameter greater than 4 cm and/or age younger than 34 years) were prospectively included in a protocol of adjuvant chemotherapy. Treatment consisted of two 3-week courses of etoposide 120 mg/m2 and cisplatin 40 mg/m2 for three consecutive days with granulocyte colony-stimulating factor support. Results: Of the 64 patients, 43 (67%) were younger than 34 years and 55 (86%) had a tumor diameter greater than 4 cm. Neutropenia and nausea and vomiting were the most frequent grade 3 or 4 toxicities (16.5% and 9.5%, respectively), apart from alopecia. After a median follow-up of 60 months (range 7 to 118), no disease relapses have occurred. A metachronous testicular carcinoma has been reported. One patient died of causes unrelated to his disease. Conclusions: The results of our study have shown that two cycles of etoposide and cisplatin is an effective and safe form of adjuvant therapy for Stage I testicular seminoma. Risk factors can be used to identify patients who could benefit from etoposide and cisplatin treatment. © 2007 Elsevier Inc. All rights reserved.

Objective: We evaluated safety and efficacy of first-line gemcitabine/carboplatin in unfit-for-cisplatin patients with advanced urothelial carcinoma and the effect on the quality of life and functional status of elderly patients (aged >70). Methods: Unfit patients had ECOG performance status (PS) ≥2, creatinine clearance <50 ml/min or comorbidities precluding cisplatin administration. Carboplatin at area under the curve of 2.5 and gemcitabine 1,250 mg/m2 were administered biweekly. Elderly patients were stratified into group 1 (no activities of daily living (ADL) or instrumental ADL dependency and no comorbidities), group 2 (instrumental ADL dependency or 1-2 comorbidities) and group 3 (ADL dependency or ≥2 comorbidities). Results: Thirty-four patients were enrolled: 68% had PS 2-3, 69% a creatinine clearance <50 ml/min and 65% had 1 or more comorbidities. There were 3 cases of grade 3 toxicity (9%). Response rate was 24% [95% confidence interval (CI) 11-41]. Median follow-up was 8 months, median progression-free survival 4.4 months (95% CI 1.03-7.75) and median overall survival 9.8 months (95% CI 4.7-14.9). Patients in geriatric assessment groups 1 and 2 had a significantly longer median progression-free survival compared to group 3 [6.9 months (95% CI 1.3-12.4) vs. 1.9 months (95% CI 0.5-3.2); p = 0.005]. Conclusion: First-line gemcitabine/carboplatin combination is active in unfit-for-cisplatin patients with advanced urothelial carcinoma. Pretreatment quality of life and geriatric assessment may be useful in selecting patients likely to benefit from this treatment. Copyright © 2008 S. Karger AG.

BACKGROUND. The toxicity of platinum-based combinations represents a common problem for patients with advanced urothelial carcinoma. The authors previously reported encouraging efficacy for the combination of carboplatin and gemcitabine in patients considered to be unfit for cisplatin-based treatment. The objective of the current multicenter Phase II study was to evaluate the safety and efficacy of the combination of gemcitabine and carboplatin as first-line treatment in unselected patients with advanced urothelial carcinoma. METHODS. Patients with previously untreated, bidimensionally measurable, inoperable or metastatic urothelial carcinoma were treated with carboplatin, area under the concentration curve of 5 (Day 1) and gemcitabine at a dose of 1000 mg/m2 (Days 1 and 8), every 21 days for a total of 6 cycles. RESULTS. Sixty patients (49 men and 11 women, with a median age of 69 yrs) were enrolled in the current study. Intent-to-treat analysis demonstrated an objective response rate (ORR) of 38.4% (95% confidence interval [95% CI], 26-51.8%) (11.7% complete responses and 26.7% partial responses). The median time to disease progression was 7.6 months (95% CI, 4.5-10.7 mos) and the median overall survival was 16.3 months (95% CI, 12-20.6 mos). The median survival was comparable to that reported for the combination of methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) according to the Memorial Sloan-Kettering Cancer Center prognostic model for patients with similar baseline prognostic features. Grade 3 or 4 toxicity (according to the National Cancer Institute Common Toxicity Criteria [version 2.0]) included anemia (18%), thrombocytopenia (23%), and neutropenia (52%), with 7 episodes of febrile neutropenia (11%) reported. Nonhematologic toxicity was rare. One toxic death occurred during the study. CONCLUSIONS. The combination of gemcitabine and carboplatin appears to have considerable activity as the first-line treatment of unselected patients with advanced urothelial carcinoma with manageable toxicity, and deserves further evaluation in this setting. © 2005 American Cancer Society.

Soft tissue lymphoma is a very rare clinical entity with varying presentation characteristics and atypical clinical and imaging features. The present report describes a patient who presented with a painless soft tissue mass on the posterolateral surface of the abdominal wall, simulating a neoplasm of mesenchymal origin. After complete surgical excision, the tumor was diagnosed as a diffuse large B-cell lymphoma. No B-symptoms were present and clinical staging did not reveal other sites of disease (stage I EA). The International Prognostic Index score was equal to 1 and classified the patient to the good risk group. Post-operatively the patient was treated with immuno-chemotherapy consisting of rituximab plus cyclophosphamide, epirubicin, vincristine and prednisolone and is currently free of disease for 10 months. The case is discussed with a brief review of the literature on the diagnosis, treatment and outcome of soft tissue lymphomas. © 2006 Taylor & Francis.

Fifty patients with multiple myeloma ≥75 years of age received primary treatment with melphalan (M) 8 mg/m2 on days 1-4, dexamethasone (D) 12 mg/m2 on days 1-4 and 17-20 and thalidomide (T) 300 mg at bedtime on days 1-4 and 17-20. This regimen was repeated every 5 weeks for three courses. Patients without evidence of disease progression received nine additional courses of MDT, but without DT on days 17-20, every 5 weeks. Sixty-two percent of patients achieved a partial response and 10% a complete response. The median time to response was 2 months. The median time to progression for all patients was 21.2 months. Deep venous thrombosis and peripheral neuropathy each occurred in 9% of patients. ©2006 Ferrata Storti Foundation.

Background and Objectives. Pure infradiaphragmatic Hodgkin's lymphoma (HL) is a rare disease. The prognostic impact of a purely infradiaphragmatic localization of this lymphoma is controversial. We aimed to evaluate the baseline clinicopathologic features, prognostic factors and outcome of a large series of consecutive patients with pure infradiaphragmatic HL. Design and Methods. We analyzed 131 patients with clinical stage I/II infradiaphragmatic HL treated with ABVD or equivalent regimens with or without radiotherapy, and compared 54 of them with 444 patients with pure supradiaphragmatic disease, who were treated at the same center. Results. Older age, clinical stage II (borderline), involvement of ≥3 sites, lymphocyte predominant histology, elevated serum β2-microglobulin and higher International Prognostic Score were more frequent in patients with infradiaphragmatic disease than in those with supradiaphragmatic disease, while nodular sclerosis was less frequent. The complete remission rate was 100%, 97% and 82% for stages I, IIA and IB, respectively. Only B-symptoms independently predicted for inferior failure-free survival, while inferior overall survival was independently associated with the involvement of ≥3 sites. At 10 years failure-free survival was 82±6% (vs. 85±2% for patients with supradiaphragmatic disease, p=0.45), overall survival was 74±8% (vs. 91±2%, p=0.0006), and disease-specific survival 87±5% (vs. 94±1%, p=0.04). In multivariate analysis the differences between infradiaphragmatic and supradiaphragmatic disease were obscured by older age and B-symptoms. Interpretation and Conclusions. Pure infradiaphragmatic HL presents with distinct clinicopathologic characteristics. The previously reported poorer outcome may be explained by the unfavorable profile of the patients rather than the infradiaphragmatic presentation per se. Patients with stage IIB disease should probably be classified as having advanced HL because of the unacceptable rate of primary refractory disease. ©2006 Ferrata Storti Foundation.

This report by an international consensus panel updates current recommendations for defining clinical response in Waldenström's macroglobulinemia (WM). The previously published response criteria incorporated parameters for monoclonal protein reduction and/or improvement of marrow and nodal involvement, and included definitions of complete and partial remissions. The criteria have been updated to include minor response and stable disease categories. In addition, the criteria now recognize that delayed responses after treatment with nucleoside analogues and biologic agents and the time point for assessing response in patients with WM should be considered so as to not miss or miscategorize a response. The new criteria should therefore help in better delineating responses to therapy in patients with WM, particularly with the wide use of nucleoside analogues and biologically based agents for this disease.

Serum levels of macrophage inflammatory protein-1 alpha (MIP-1α) and bone remodelling markers were evaluated in 38 patients with Waldenström macroglobulinaemia (WM) and correlated with clinical and laboratory variables. MIP-1α was elevated in WM; untreated patients had higher MIP-1α levels than patients in remission or with active disease after treatment. MIP-1α correlated with increased bone resorption, β2- microglobulin and splenomegaly. Receptor activator of nuclear factor-κB ligand serum levels were elevated in WM patients; the subsequent increased bone resorption was balanced by a comparable elevation of osteoprotegerin production and bone formation. These findings may explain the absence of lytic lesions in WM patients and suggest a potential role of MIP-1α in WM. © 2006 Blackwell Publishing Ltd.

Brain metastases in patients with epithelial ovarian cancer (EOC) have an estimated incidence of 0.3-1.9% and are isolated in up to 50% of these patients. The risk factors and the prognostic significance of isolated central nervous system (CNS) relapse in patients with EOC who received primary treatment with platinum and paclitaxel have not been identified. We conducted a retrospective study in patients with EOC who relapsed with isolated brain metastases and report our experience. Two hundred sixty-seven patients with stages III and IV EOC, in clinical complete remission after first-line treatment with platinum and paclitaxel, were included in our analysis. After a median follow-up of 65 months, 150 patients had relapsed. Eight patients (5%) had isolated brain metastases. Patient and disease characteristics did not differ among patients who relapsed with isolated brain metastases and those with relapse outside the CNS. Median time to first disease relapse, overall survival, and survival after relapse did not differ significantly between patients with brain metastases and those with relapse outside the CNS. Two patients have died 6 and 12 months after the diagnosis of brain metastases, and 5 patients are alive 4-35 months after the diagnosis of isolated brain metastases. Three patients remain free of disease 4-18 months after treatment with radiotherapy and systemic chemotherapy for their CNS metastatic disease. Patients with isolated brain metastases have comparable survival to patients with relapse outside the CNS, and long-term remission can be achieved in some cases, provided that systemic chemotherapy is added to local treatment. © 2006, Copyright the Authors.

The adverse prognostic role of cytogenetic abnormalities has recently been established in plasma cell dyscrasias. Modern techniques such as fluorescence in situ hybridization and comparative genomic hybridization have revealed a higher incidence of cytogenetic abnormalities in patients with multiple myeloma (MM) compared to conventional cytogenetics. Hypodiploidy and chromosome 13 abnormalities are found in more than 50% of myeloma patients, representing well known factors with adverse prognosis. Rearrangements involving the switch regions of immunoglobulin heavy chain (IgH) gene at 14q32 with various partner genes represent the most common structural abnormalities, having an incidence of 70% in MM. Structural abnormalities of chromosomes 17 and 8 involving the p53 and c-myc genes are considered to be less frequent events, but carry a poor prognosis. New therapeutic approaches such as non-myeloablative allotransplantation and modern therapeutic agents (thalidomide, lenalidomide, and bortezomib) and their combinations give promise for an improved therapeutic management of patients with MM. The detection of t(4;14), t(14;16), deletion of chromosome 13 on metaphase analysis, or deletion of p53 by FISH will define high-risk prognostic groups that are not generally controlled with high-dose melphalan and autologous stem cell transplantation (ASCT), and should therefore be treated with more investigational therapies. Alternatively, eligible patients who do not have these poor risk factors are more likely to benefit from a high-dose, melphalan-based, regimen followed by ASCT. © 2006 Taylor & Francis.

Purpose: The cellular inhibitor of apoptosis protein (cIAP) is regarded as an important prognostic biomarker in cancer. Here, we sought to determine the prognostic value of cIAP protein levels in epithelial ovarian cancer using a novel method of compartmentalized in situ protein analysis. Methods: A tissue array composed of 150 advanced-stage ovarian cancers, treated with surgical debulking followed by platinum/paclitaxel-based combination chemotherapy, was constructed. For evaluation of protein expression, we used an immunofluorescence-based method of automated in situ quantitative measurement of protein analysis. Results: The mean follow-up time for the entire cohort was 34.4 months. Patients with tumors bearing high cIAP membranous expression had a 3-year survival rate of 31% compared with 73% for patients with low cIAP expressing tumors (P = 0.0020). In multivariable analysis, adjusting for well-characterized prognostic variables, low membranous cIAP expression level was the only significant prognostic factor for overall survival. Conclusions: Our results indicate that cIAP protein levels have prognostic value in ovarian cancer patients. Modulation of cIAP levels may improve clinical outcome in ovarian cancer. Copyright © 2006 American Association for Cancer Research.

Purpose. To assess the prognostic and predictive significance of HER-2 overexpression and high expression of VEGF in high-risk patients with breast cancer treated with dose-dense sequential chemotherapy. Patients and methods. From June 1997 until November 2000, 595 patients were randomized to three cycles of epirubicin (E) 110 mg/m2 followed by three cycles of paclitaxel (T) 250 mg/m2 followed by three cycles of "intensified" CMF (cyclophosphamide 840 mg/m2, methotrexate 47 mg/m2 and fluorouracil 840 mg/m2) or to four cycles of E, followed by four cycles of CMF. HER-2 was assessed by immunohistochemistry (IHC) in 394 patients, and by fluorescence in situ hybridization (FISH) in cases scored as 2+ by IHC. VEGF was evaluated in 323 patients by IHC. Results. HER-2 overexpression was detected in 123 patients (31%) and high expression of VEGF in 233 (72%). The rate of HER-2 overexpression was significantly higher in patients with positive VEGF staining (35% vs. 21%, p = 0.02). Overexpression of HER-2 was significantly associated with negative hormonal status, high histologic grade and larger tumors. HER-2 overexpression was a significant negative predictor of DFS (p = 0.002), but not of OS. Adjusting for HER-2 overexpression, DFS and OS did not significantly differ between treatment groups. Positive VEGF staining was not associated with receptor status, number of positive nodes, grade, tumor size, incidence of relapse or death. Conclusions. For both treatments, HER-2 overexpression was a significant negative prognostic factor for DFS but not for OS, while high expression of VEGF was not significantly associated to either DFS or OS. No predictive ability of HER-2 status or VEGF overexpression for T treatment was evident. © Springer 2006.

Primary lymphoma of the upper urinary tract is an extremely rare entity without specific clinical or laboratory findings. Thus, this particular diagnosis is rarely anticipated and might well be reached only after nephroureterectomy. We describe a patient with primary follicular and diffuse follicle center lymphoma arising in the renal pelvis that was treated with surgery and postoperative immunochemotherapy. Furthermore, we review the literature regarding the treatment and outcome of this rare disease.

Background: The pulmonary side-effects induced by novel antineoplastic agents have not been well characterized. Methods: To further investigate this topic, relevant English and non-English language studies were identified through Medline. For our search we used the generic names of novel cytotoxic or non-cytotoxic antineoplastic agents and the key phrases pulmonary/lung toxicity, dyspnea, pneumonitis, acute lung injury, acute respiratory distress syndrome and alveolar damage. The references from the articles identified were reviewed for additional sources. Abstracts from International Meetings were also included. Furthermore, information was obtained from the Pneumotox® website, which provides updated knowledge on drug-induced respiratory disease as well as from pharmaceutical websites. Results: Most novel antineoplastic drugs may induce pulmonary toxicity, which involves mainly the parenchyma, and less frequently the airways, pleura or the pulmonary circulation. Furthermore, a subset of these agents impairs pulmonary function tests. The exact incidence of lung toxicity remains unclear. The most common patterns consist of dyspnea without further details and infiltrative lung disease (ILD), denoting changes in the interstitium or alveoli. The diagnosis is one of exclusion. ILD is usually benign and responds to appropriate treatment; however, fatalities have been reported. Conclusions: Clinicians should be aware of the potential of most novel antineoplastic agents to cause lung toxicity. A high index of suspicion is required if these are combined with other cytotoxic drugs or radiation. © 2005 European Society for Medical Oncology.

Monoclonal IgM-related neuropathies constitute a heterogeneous group of disorders, which are generally poorly responsive to treatment. Rituximab, a chimeric monoclonal antibody against the CD20 molecule, has been used with success in patients with neuropathy and monoclonal IgM with anti-MAG or anti-GM1 ganglioside activity. Based on this observation, four patients were treated with IgM-related neuropathy with rituximab. Between January 1999 - December 2000, four patients with IgM-related neuropathy (one with chronic inflammatory demyelinating polyneuropathy (CIDP) and three with sensorimotor demyelinating neuropathy) were treated with rituximab. Rituximab was administered at a standard dose of 375 mg m-2 iv weekly for a consecutive 4 weeks; 3 months later, four additional weekly courses were administered to patients who did not experience deterioration of their neuropathy symptoms. Neurological evaluation was performed before each rituximab infusion and at 1 week and 2 months after last infusion and every 6 months the following years; including motor (MRC in six muscle groups, 9-hole peg test, 10m walk, hand grip strength), sensory neuropathy (vibration threshold and sensory subjective score) assessment. Neurophysiological parameters were also assessed (MNCV, SNCV, CMAP, SNAP). Strength improved in three of four patients; including the patient with CIDP. This patient developed a significant worsening of her weakness 3 weeks after the initiation of rituximab. This phenomenon coincided with a serum monoclonal IgM flare and resolved spontaneously 1 week later. Her improvement is ongoing for more than 5 years. Considering neurophysiological parameters, two patients showed a slight improved regarding conduction velocities and CMAP (10%) and the patient with IgM flare had a transient worsening of conduction velocities followed by improvement. In conclusion, rituximab is a safe and well-tolerated treatment which may be effective in some patients with IgM-related neuropathy. © 2006 Taylor & Francis.

Urothelial cancer is a common malignancy. The management of patients with recurrent disease after cystectomy or initially metastatic or unresectable disease represents a therapeutic challenge. Systemic chemotherapy prolongs survival but long-term survival remains infrequent. During recent years there has been improvement due to the use of novel chemotherapeutic agents, mainly gemcitabine and the taxanes. The long-considered-standard MVAC has been challenged by combinations showing more favourable toxicity profiles and equal (gemcitabine-cisplatin) or even improved (dose-dense, G-CSF-supported MVAC) efficacy. Specific interest has also been generated in specific groups of patients (elderly patients, patients with renal function impairment or comorbidities), who are not fit for the standard cisplatin-based chemotherapy but can derive significant benefit from carboplatin- or taxane-based treatment. Retrospective analyses have enabled the identification of groups of patients with different prognoses, who possibly require different therapeutic approaches. Modern chemotherapy offers a chance of long-term survival in patients without visceral metastases, possibly in combination with definitive local treatment. Finally, the progress of targeted therapies in other neoplasms seems to be reflected in advanced bladder cancer by recent studies indicating that biological agents can be combined with modern chemotherapy. The true role of such therapies is currently being evaluated. © 2006 Oxford University Press.

Waldenström macroglobulinemia (WM) is a B-cell disorder characterized by the infiltration of lymphoplasmacytic cells into bone marrow and the presence of an IgM monoclonal gammopathy. As part of the Third International Workshop on WM, held October 7 to 10, 2004 in Paris, France, a consensus panel charged with providing treatment recommendations for WM updated its recommendations on both frontline and salvage therapies. The panel considered encouraging results from recent studies that addressed the use of extended-dose rituximab as well as other treatment options: therapy with either nucleoside analogs and alkylator agents, rituximab in combination with nucleoside analogs, nucleoside analogs plus alkylator agents, or combination chemotherapies, such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or cyclophosphamide and dexamethasone. The panel determined that these were reasonable treatment options for WM patients and such therapeutic approaches were likely to yield results that are at least as good as if not better than the currently recommended use of single-agent alkylator, nucleoside analog, or standard-dose rituximab therapy. Such approaches were deemed to be reasonable treatment for WM patients in both the upfront and salvage settings, though randomized studies addressing the efficacy and toxicity of such novel approaches over previously established standard of care options are needed. © 2006 by The American Society of Hematology.

Purpose.: Ovarian clear-cell carcinomas (OCCC) are known to be possibly resistant to platinum-based chemotherapy and to have a poorer prognosis with respect to other subtypes of epithelial ovarian cancer (EOC). This study was undertaken to compare response and survival to platinum-based chemotherapy between patients with advanced stage III and IV OCCC and serous EOC (sEOC). Patients and methods.: A retrospective analysis was performed in patients with advanced stage of OCCC treated with first-line platinum-based chemotherapy in the context of several study protocols of the Hellenic Cooperative Oncology Group (HeCOG) between 1/2/1987 and 31/10/2003. The outcome was compared to that of patients with sEOC treated according to the same protocols during the same study period. Results.: One hundred and five patients (35 stage III and IV OCCC, 70 stage III and IV sEOC) treated with platinum-based chemotherapy were analyzed. The overall response rate for OCCC was 45% (complete response 25%) (95% CI, 23.1% to 68.5%) and 81% (complete response 46%) (95% CI, 67.4% to 91.1%) for sEOC. The overall response rate was significantly higher for sEOC (P = 0.008). In the subgroup of stage III patients, the rate of complete responders was higher among sEOC patients (P = 0.023). After a median follow-up of 61.1 months, median survival and time to tumor progression were not significantly different between the two groups (25.1 months [95% CI 11.7 to 38.5 months] versus 49.1 months [95% CI 36.5 to 61.6 months], P = 0.141, 12.0 months [95% CI 6.5 to 17.3 months] versus 18.0 months [95% CI 14.7 to 21.6 months], P = 0.384, respectively). Conclusion.: Patients with OCCC have significantly lower response to platinum-based first-line chemotherapy compared to patients with sEOC. This low response to platinum-based chemotherapy was not translated in significantly shorter survival. The current study outcomes are provocative and suggest that a new strategy for chemotherapy in OCCC should be adopted, possibly one that focuses on new agents without cross-resistance to platinum agents. © 2006 Elsevier Inc. All rights reserved.

The cause of the polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder and skin changes (POEMS) syndrome is currently unknown, but increased levels of vascular endothelial growth factor (VEGF) appear to play a pathogenetic role. Osteosclerotic bone lesions are a characteristic finding in POEMS, but there are no data about the specific role of various molecules that control bone remodeling in patients with POEMS. Serum levels of angiogenic cytokines (VEGF, angiogenin, angiopoietin-2, and basic fibroblast growth factor) along with a series of bone remodeling indices (C-telopeptide of type I collagen, bone-alkaline phosphatase [bALP], osteocalcin [OC], soluble receptor activator of nuclear factor-κB ligand [RANKL], osteoprotegerin [OPG], and macrophage inflammatory protein-1α) were measured in 2 patients with POEMS before and after high-dose therapy (HDT) with autologous stem cell transplantation and in age- and sex-matched controls. Increased VEGF levels before HDT were reduced significantly after treatment, although levels of the other angiogenetic factors did not differ from that of controls and were less influenced by HDT. Serum RANKL levels were increased before HDT, whereas OPG levels were within the levels of healthy controls, resulting in an abnormal soluble RANKL to OPG ratio. Levels of bone resorption markers (C-telopeptide of type I collagen) were very low or undetectable before HDT, although bALP and OC levels were similar to that of controls. After HDT, soluble RANKL levels decreased, OPG remained rather stable, bone resorption markers increased to levels of normal individuals, bALP levels were rather unchanged, and OC levels increased. Decreasing VEGF levels parallel clinical improvement, and the restoration of normal bone metabolism follows HDT.

Ovarian cancer is a leading cause of death from gynecological cancer. Although most patients will experience remission of their disease, following cytoreductive surgery and platinum (± paclitaxel) chemotherapy, relapse will occur in about 80% of cases with FIGO stages III and IV disease. Treatment of recurrent ovarian cancer represents a challenge. Cure is rare but long-term survival can be achieved in a significant proportion of patients. Treatment-free interval after first-line platinum-based chemotherapy determines sensitivity to platinum rechallenge. Nevertheless, other factors, such as symptoms, tumor bulk, ECOG PS and patients' preferences can also aid decision making in this setting. The recent ICON4/AGO and GCIC studies showed that combination of carboplatin with paclitaxel or gemcitabine are superior to carboplatin monotherapy in patients with platinum-sensitive disease, but at the expense of additional toxicity. Platinum refractory disease is associated with poor prognosis and monotherapy with a non-platinum agent, such as liposomal doxombicin, topotecan or a taxane is recommended. Biological agents targeting various components on cancer cells, such as vascular endothelial growth factor (VEGF), growth factors and stromal elements, are under investigation as adjuncts to chemotherapy. In addition, selected patients may benefit from surgery at recurrence, but they represent the minority of patients with relapsed ovarian cancer. © 2006 Bentham Science Publishers Ltd.

New uniform response criteria are required to adequately assess clinicaloutcomes in myeloma. The European Group for Blood and Bone MarrowTransplant/International Bone Marrow Transplant Registry criteria have beenexpanded, clarified and updated to provide a new comprehensive evaluationsystem. Categories for stringent complete response and very good partialresponse are added. The serum free light-chain assay is included to allowevaluation of patients with oligo-secretory disease. Inconsistencies in priorcriteria are clarified making confirmation of response and disease progressioneasier to perform. Emphasis is placed upon time to event and duration ofresponse as critical end points. The requirements necessary to use overallsurvival duration as the ultimate end point are discussed. It is anticipatedthat the International Response Criteria for multiple myeloma will be widelyused in future clinical trials of myeloma.

Background.: Neoplastic meningitis in patients with carcinoma of the uterine cervix is unusual in the course of their diseases. Even more unusual are intramedullary spinal metastases. Case.: We report the case of a 64-year-old woman who presented with leptomeningeal and intramedullary spinal cord metastases from a grade 2 squamous cell cancer of the uterine cervix. This is just the second case of intramedullary metastases from cervical carcinoma. Conclusion.: Neoplastic meningitis or intramedullary metastases are extremely rare in the course of uterine cervix carcinoma. Nevertheless, when indicated by symptoms, patients should undergo MRI of the brain and/or spine and have a lumbar puncture performed, for the diagnosis of this devastating complication. Treatment is mainly palliative but may offer symptom relief. © 2006.

There are limited reports of young patients with multiple myeloma (MM) who presented with multiple lytic bone lesions but without intervening infiltration of bone marrow, a pattern consisting of macrofocal MM. In order to clearly define the clinical and laboratory features and outcome of such patients, a retrospective analysis was performed of symptomatic patients with MM ≤40 years of age at diagnosis who received primary treatment over a 20-year period. Ten of 51 patients fulfilled the criteria of macrofocal MM. When compared to patients with typical MM, patients with macrofocal pattern were less anemic, none had hypercalcemia, renal impairment, elevated serum LDH or stage 3 according to the International Staging System (ISS). Patients with macrofocal MM usually had preserved the uninvolved immunoglobulins. An objective response to primary treatment was noted in 55% of patients with macrofocal MM and in 50% of patients without this pattern. The median survival of patients with typical MM was 57 months and is projected to exceed 8 years in patients with macrofocal MM (p = 0.087). With macrofocal MM despite multiple lytic bone lesions, patients have features of low tumor burden and improved survival when compared with young patients with typical MM.

Osteonecrosis of the jaw (ONJ) has been associated with the use of pamidronate and zoledronic acid. ONJ was assessed prospectively since July 2003 in 202 patients with multiple myeloma (MM) who received bisphosphonates since April 1995. Fifteen patients (7.4%) developed ONJ. The median time of exposure to bisphosphonates was 39 months for patients with ONJ compared to 28 months (p=0.048) for patients with no ONJ. The cumulative hazard of developing ONJ was significantly higher in patients treated with zoledronic acid alone than in those treated with pamidronate alone/pamidronate+zoledronic acid/zoledronic acid+ibandronate sequentially (1% at 1 year and 15% at 4 years vs. 0% and 5%, p=0.003). In conclusion, the risk of ONJ is increased with time of exposure and probably with the use of zoledronic acid. ©2006 Ferrata Storti Foundation.

To investigate the molecular mechanisms of action of the nitrogen mustard melphalan in patients treated for multiple myeloma, the in vivo induction and repair of melphalan-induced DNA damage was measured in genes with different transcriptional activity (b-actin > p53 > N-ras > d-globin) from leukocytes of 20 multiple myeloma patients following chemotherapeutic administration of high-dose melphalan (200 mg/m2) and autologous blood stem cell transplantation. Heterogeneous repair was found among the studied genes. The extent of repair was always in the order: b-actin > p53 > N-ras > d-globin, correlating with the gene transcriptional state. Similar findings were obtained using peripheral blood mononuclear cells (PBMC) from healthy volunteers following in vitro treatment with melphalan, indicating that these results are not malignant disease-specific. Following in vitro treatment of PBMC from healthy volunteers with α-amanitin, an inhibitor of RNA polymerase II that can also induce condensation of chromatin structure, a significant inhibition of the removal of melphalan-induced damage in the three active genes but not in the silent d-globin gene was found, suggesting that transcription and/or chromatin structure may play important roles in the preferential DNA repair. When the in vivo DNA damage formation and repair in multiple myeloma patients following chemotherapeutic administration of melphalan was measured in the two strands of the active genes, no strand bias was found, indicating that the global genome repair subpathway of nucleotide excision repair may play a crucial role in the repair of these adducts. These results were also confirmed in PBMC from healthy volunteers following in vitro treatment with melphalan. Using micrococcal nuclease digestion of nuclei isolated from PBMC of multiple myeloma patients before the chemotherapeutic treatment, as well as from PBMC of healthy volunteers, we probed the chromatin structure in each gene and found that the "looseness" of the chromatin structure correlated with the levels of the gene-specific repair, being again in the order: b-actin > p53 > N-ras > d-globin. To conclude, the in vivo gene-specific repair of melphalan-induced damage in humans is greatly affected by the local chromatin structure. © 2006 Elsevier B.V. All rights reserved.

99mTc-2-methoxyisobutylisonitrile (99mTc-MIBI) scintigraphy has been suggested in multiple myeloma (MM) patients. According to the International Staging System (ISS), serum b2-microglobulin (Sβ2M) and serum albumin (SA) are dominant predictive factors and different cut-off values of these factors can separate patients into various stages of the disease. The purpose of this study was to assess the relationship between ISS staging, by Sβ2M and SA, and the 99mTc-MIBI scan findings. Twenty-five MM patients have been studied. Eighteen patients were at stage I, three at stage II and four at stage III of MM. 99mTc-MIBI scans were obtained and scored according to intensity (I) and extent (E) of the radiotracer uptake. A summed score (S) for the 99mTc-MIBI scan was calculated for each patient. A statistically significant negative correlation between E, I and S uptake scores versus the SA levels (P=0.004, 0.049 and 0.018 respectively), as well as a statistically significant positive correlation between E and S scores and the Sβ2M levels (P=0.012 and 0.032) were detected. A statistically significant difference between the E and S uptake scores among the MM patients examined for every stage separately was also found (P=0.007 and 0.024 respectively). The gradual increase of the E and S scores across the three stages of MM was also significant (P=0.003 and 0.021 respectively), despite the relatively small number of patients in stages II and III. In seven patients who died at the end of the follow-up period all three scores were significantly increased as compared to the scores of the patients who remained alive at that time. In conclusion, this study provides additional evidence that 99mTc-MIBI scan not only reflects myeloma disease activity in bone marrow but it is also well correlated with the Sβ2M and SA levels according to ISS.

Background: Surgery can cure a significant percentage of ovarian carcinoma confined to the pelvis. Nevertheless, there is still a 10-50% recurrence rate. We administered paclitaxel/carboplatin as adjuvant treatment in early-stage ovarian carcinoma. Methods: Patients with stages Ia or Ib, Grade 2 or 3 and Ic to IIb (any grade) were included. Patients were treated with 4 cycles of Paclitaxel 175 mg/m2 and Carboplatin [area under the curve (AUC) 6 (Calvert Formula)] every 3 weeks. Results: Sixty-nine patients with no residual disease following cytoreductive surgery and minimal or modified surgical staging were included in this analysis. Grade 3 or 4 neutropenia occured in 29.9% of patients, while neutropenic fever was reported in 4.5%. Neurotoxicity (all Grade 1 or 2) was reported in 50% of cases. Median follow-up was 62 months. 5-year overall survival (OS) and relapse-free survival (RFS) were: 87% (95% confidence intervals [CI]: 78-96) and 79% (95% CI: 69-89), respectively. Significantly fewer patients with stages Ic-IIb and tumor grade 2 or 3 achieved a 5-year RFS than patients with only one of these two factors (73% vs 92%, p = 0.03). Conclusion: Paclitaxel/Carboplatin chemotherapy is a safe and effective adjuvant treatment in early-stage ovarian carcinoma Patients with stages Ic-IIb and tumor grade 2 or 3 may benefit from more extensive treatment. © 2006 Bamias et al; licensee BioMed Central Ltd.

Background: There is limited information about the benefit from systemic chemotherapy in non-pure Transitional Cell Carcinomas (TCCs) of the urothelial tract. In this study the efficacy of platinum-based chemotherapy in patients with pure squamous or mixed carcinomas was retrospectively analysed and compared with that in pure TCCs. Patients and Methods: Analysis included 446 consecutive patients treated with platinum-based chemotherapy for advanced or metastatic urothelial cancer. There were 389 (87%) patients with pure TCC, 15 (3.5%) with pure Squamous Cell Carcinomas (SCC) and 42 (9.5%) patients had mixed histology (TCC+SCC) tumors. Results: There were no statistically significant differences in baseline characteristics (gender, PS, haemoglobin, sites of metastases) although disease in the pelvis was more frequent in mixed tumors than in pure TCCs (46% vs. 30%, p=0.034). Median survival for patients with TCC histology was 11.3 months, for SCC patients 13.6 months and 10.4 months for patients with mixed histology (p=0.720). Response rates were 44% for patients with TCC, 27% for patients with SCC and 34% for mixed histology patients (p=0.210). Multivariate analysis showed that presence of visceral metastases and poor performance status, were associated with worse prognosis in mixed histology tumors. Conclusion: Non-transitional histology does not predict for an inferior survival after platinum-based chemotherapy for advanced urothelial carcinoma. Well-known prognostic factors in transitional cell carcinomas were also associated with prognosis in mixed carcinomas.

The aim of this retrospective study was to illustrate the clinicopathologic data and the treatment results in patients with primary gastrointestinal tract non-Hodgkin's lymphoma (GI NHL). Among 810 patients with NHL, 128 cases (15.8%) were diagnosed as primary GI tract NHL. There were 79 males and 49 females with median age of 62 years. The most common primary site was the stomach (68%). Overall, 67.2% of the patients were in stages I-II, and 32.8% in stages III-IV. Simultaneous involvement of the GI tract and other extranodal sites was observed in 26 patients (20%). Extranodal marginal zone B-cell lymphoma (MZBL) (i.e., low-grade lymphoma of mucosa-associated lymphoid tissue type) accounted for 48.4% of lymphomas. Aggressive lymphomas (diffuse large B-cell lymphoma [DLBL]) accounted for 44.5%. Eighty-three patients (67.5%) achieved complete response (CR), either by surgery (43/ 43 patients, 17 with DLBL and 25 with MZBL) or by primary chemotherapy (40/64 patients, 22 with DLBL and 17 with MZBL). Sixty-two patients remain in CR; 33/43 after surgical resection (13/17 with DLBL and 20/25 patients with MZBL), and 29/40 after only chemotherapy (18/22 with DLBL and 10/17 with MZBL). The major prognostic factor for outcome in the present study was the stage of the disease. Patients with localized lymphoma (stage I and II) had significantly longer DFS and OS (DFS and OS at 3-year: 83% and 87%, respectively) than patients with extended disease (stage III and IV) (DFS and OS at 3-year: 46% and 60%, respectively) (P < 0.0001). The International Prognostic Index (IPI) for patients with aggressive lymphomas was prognostic only for DFS (79% for low-risk patients [IPI score 0-1] vs 49% for higher risk groups [IPI score 0-1] at 3-year, P = 0.0131).

Purpose: Waldenström's macroglobulinemia (WM) is a lymphoplasmacytoid lymphoma characterized by a relatively indolent course with median survival ranging from 5 years to 10 years in different series. Several clinical and laboratory variables have been associated with inferior survival, such as advanced age, hyperviscosity, presence of cytopenia, and hypoalbuminemia. Recent data indicate that serum β2-microglobulin (β2M) might also be significant. The purpose of our study was to assess possible correlations of β2M with clinical and laboratory variables and to further evaluate its association with cause-specific and overall survival (OS) of patients with WM requiring treatment. Patients and Methods: We analyzed 124 patients with WM with an available pretreatment value of β2M. Median age was 70 years (range, 28-89 years), and median survival was 105 months. Multiple clinical and laboratory parameters were evaluated for their possible correlation with OS. Results: Patients with older age, anemia, thrombocytopenia, hypoalbuminemia, and higher creatinine levels had significantly greater serum β2M levels. This variable was associated with impaired cause-specific survival and OS in the whole group of patients and in patients aged ≤ 70 years. More specifically, OS for all patients according to serum β2M > 4 mg/dL versus ≤ 4 mg/dL was 79 months versus 115 months (P = 0.01). Conclusion: Our data provide further evidence that high β2M levels are an important parameter associated with inferior OS and cause-specific survival of patients with WM requiring treatment. This parameter may be used to stratify patients involved in prospective clinical trials.

Dickkopf-1 (DKK-1) protein, a soluble inhibitor of Wnt signalling, has been implicated in the pathogenesis of myeloma bone disease through the suppression of osteoblast differentiation. In this study, serum concentrations of DKK-1 were measured in 50 myeloma patients (32 at diagnosis and 18 before and after autologous stem cell transplantation (ASCT), 18 patients with monoclonal gammopathy of undetermined significance (MGUS), and 22 healthy controls. Serum DKK-1 levels were increased in MM at diagnosis compared with MGUS (mean ± SD: 67 ± 54 ng/mL vs. 38 ± 13 ng/mL; p = 0.006) and controls (31 ± 11 ng/mL; p = 0.02), while there was no difference between MGUS patients and controls. Although patients with stage 2 and 3 myeloma had higher DKK-1 values than stage 1 patients (79 ± 63 vs. 40 ± 13; p = 0.005), no significant correlation between serum DKK-1 and myeloma bone disease was observed. Myeloma patients before ASCT also had increased levels of DKK-1 (63 ± 77 ng/mL; p = 0.03) compared with controls, supporting the notion that DKK-1 may be responsible for the suppressed osteoblast activity even in patients with low tumor burden. After ASCT, there was a sustained decrease in DKK-1 levels over time, while bone formation markers elevated, suggesting that the reduction of DKK-1 levels after ASCT may correlate with the normalization of osteoblast function. These results could provide the basis for developing agents that block DKK-1, thus restoring osteoblast function and counteracting the increased osteoclastogenesis observed in myeloma. © 2006 Wiley-Liss, Inc.

Introduction: Glycodelin and survivin are key polypeptide regulators of cellular proliferation, apoptosis and angiogenesis. In view of contradictory reports on their functional role in tumors, we studied their transcriptional levels in localized breast cancer. Patients and methods: Glycodelin and survivin messenger ribonucleic acid (mRNA) was isolated and amplified by quantitative reverse-trancription PCR from paraffin-embedded breast carcinomas of 275 women. A normalized score was calculated by the use of GAPDH, RPL37A reference genes and was correlated with clinicopathologic/molecular parameters and patient outcome. Results: A total of 272 patients were eligible, most harbored stage III node-positive breast carcinomas larger than 2 cm. Glycodelin mRNA was expressed in 68 patients (25%), more frequently in premenopausal women (P = 0.01) and those with HER2 mRNA-positive tumors (P = 0.02). Survivin mRNA was present in 263 tumors (97%) and its levels correlated significantly with high nuclear grade, VEGF mRNA and p53 mRNA presence (P < 0.05). At a median follow-up of 64 months, neither glycodelin nor survivin mRNA expression demonstrated prognostic utility for overall or disease-free survival at univariate and multivariate analysis. Conclusions: Glycodelin and survivin transcriptional activity are associated with adverse clinicopathologic and molecular characteristics of node-positive primary breast cancer but do not predict patient outcome. Further study is needed for illumination of their functional roles in tumorigenesis. © 2006 Springer Science+Business Media, LLC.

Background: Young age has been reported to be a favorable prognostic factor in ovarian cancer. The aim of the present study was to investigate the characteristics of ovarian cancer presenting in patients aged ≤40 and assess the prognostic significance of young age. Methods: Data from 591 consecutive ovarian cancer patients, including 37 subjects (6.3%) aged ≤40, who were treated postoperatively with platinum-based chemotherapy in our institution were retrospectively reviewed. Results: In our series, age ≤40 did not show an independent association with overall (p = 0.542) or progression-free survival (p = 0.334). Nonetheless, it was correlated with low tumor grade (p = 0.009) and small volume of residual disease after primary surgery (p = 0.020), while there was a nonsignificant trend for correlation with performance status 0 (p = 0.052). Stratified analysis showed that age ≤40 was associated with improved overall survival in the subgroups of serous histology and stage IIC-IV disease; however, multivariate analyses failed to identify age as an independent predictor of survival within either subgroup (p = 0.079 and p = 0.585, respectively). Conclusions: Age ≤40 was not an independent prognostic factor in our analysis.The survival advantage of young patients may be attributed to the association with low tumor grade, more complete surgical debulking and better performance status. Copyright © 2006 S. Karger AG.

Background: The deleted in colorectal cancer (DCC) protein, the product of DCC tumor suppressor gene, is frequently altered in cancer. Preclinical data demonstrate that DCC regulates β-catenin levels. Here, we sought to determine the association of DCC with β-catenin protein levels, clinicopathological parameters and patient outcome in ovarian cancer using a method of in situ compartmentalized protein analysis. Methods: A tissue array composed of 150 advanced-stage ovarian cancers, treated with surgical debulking and platinum-paclitaxel (Taxol) combination chemotherapy, was constructed. For evaluation of protein expression, we used an immunofluorescence-based method of automated in situ quantitative measurement of protein analysis (AQUA). Results: One hundred and twelve patients (74%) had sufficient tissue for AQUA. The median follow-up time for the entire cohort was 33 months. Patients with low nuclear DCC expression had a 3-year progression-free survival (PFS) rate of 0% compared with 33% of those with high DCC expression (P = 0.0067). In multivariate analysis, low nuclear DCC expression level retained its prognostic significance for PFS. Between DCC and β-catenin, a significant relationship was found, where tumors with low DCC had low β-catenin and vice versa (P = 0.003). Conclusions: Low nuclear DCC levels predict for poor patient outcome inepithelial ovarian cancer. DCC may exert its antitumor function, in part, through regulation of β-catenin levels. © 2006 Oxford University Press.

The effect of bortezomib on bone remodelling was evaluated in 34 relapsed myeloma patients. At baseline, patients had increased serum concentrations of dickkopf-1 (DKK-1), soluble receptor activator of nuclear factor-κB ligand (sRANKL), sRANKL/osteoprotegerin ratio, C-telopeptide of type-I collagen (CTX) and tartrate-resistant acid phosphatase isoform-5b (TRACP-5b); bone-alkaline phosphatase and osteocalcin were reduced. Serum DKK-1 correlated with CTX and severe bone disease. Bortezomib administration significantly reduced serum DKK-1, sRANKL, CTX, and TRACP-5b after four cycles, and dramatically increased bone-alkaline phosphatase and osteocalcin, irrespective of treatment response. This is the first study showing that bortezomib reduces DKK-1 and RANKL serum levels, leading to the normalisation of bone remodelling in relapsed myeloma. © 2006 The Authors.

Background: Synchronous presentation of more than one germ cell tumours of different histology in the same patient is considered to be very rare. In these cases of multiple germ cell tumours, strong theoretical and clinical data suggest an underlying common pathogenetic mechanism concerning genetic instability or abnormalities during the pluripotent embryonic differentiation and maturation of the germ cell. Case presentation: A 25 year-old young man presented with an enlarging, slightly painful left cervical mass. Despite the initial disorientation of the diagnosis to a possible thyroid disorder, the patient underwent complete surgical resection of the mass revealing mediastinal choriocarcinoma. Subsequent ultrasound of the scrotum indicated the presence of a small lobular node in the upper pole of the left testicle and the patient underwent radical left inguinal orchiectomy disclosing a typical seminoma. Based on these results, the patient received 4 cycles of Bleomycin, Etoposide and Platinum chemotherapy experiencing only mild toxicity and resulting in complete ongoing clinical and biochemical remission. Conclusion: The pathogenesis of concurrent germ cell tumours in the same patient remains an area of controversy. Although the genetic instability of the pluripotent germ cell offers an adequate explanation, the possibility of metastasis from the primary, less differentiated tumour to a distant location as a more mature subtype cannot be excluded. Possible development of a metastatic site of different histology and thus biological behaviour (e.g choriocarcinoma) should be anticipated. Furthermore, urologists, pathologists and medical oncologists should be meticulous in the original pathological diagnosis in these patients, since there is a significant frequency of germ cell tumours with mixed or overlapping histological elements with diverse potential of evolution and differentiation. © 2006 Mountzios et al; licensee BioMed Central Ltd.

Carboplatin-related hypersensitivity reactions, frequently encountered in the heavily pretreated subpopulation of patients with gynecologic malignancies, can be severe and even potentially lethal - precluding these patients from an effective salvage treatment. We describe our experience in the management of such reactions and the application of a pretreatment protocol with corticosteroids, antihistamines and a slow infusion rate in order to safely re-administer carboplatin to the above patients. From 1998 to 2004, twenty patients developed an allergic reaction to carboplatin. Sixteen of them (80%) suffered from ovarian cancer. Upon resolution of the acute reaction, thirteen patients were pretreated according to our protocol and were re-exposed to carboplatin. Fifteen patients experienced the reaction during second-line carboplatin-based treatment and 5 patients after 3 or more regimens. Fifteen of the reactions (75%) were severe. Thirteen patients were re-treated with carboplatin after the application of our protocol, all of them successfully, even though 10 patients (77%) experienced minor symptoms during subsequent courses. On the contrary, only one of the 6 patients who were re-treated without the application of the protocol was able to receive further platinum-based treatment. In conclusion, pretreatment with corticosteroids, antihistamines and a slower infusion rate may make re-treatment possible in patients having experienced hypersensitivity to carboplatin. © E.S.I.F.T. srl - Firenze.

The aim of this study was to elucidate the clinicopathological and immunohistochemical prognostic factors of patients with ovarian carcinosarcoma treated with radical surgery and postoperative chemotherapy. During a 6-year period, nine patients with ovarian carcinosarcoma were referred to our institution. Tissue blocks were reviewed and sections containing both carcinomatous and sarcomatous elements were stained for epithelial membrane antigen (EMA), vimentin, vascular endothelial growth factor (VEGF), CD45RO, c-erbB-2, p53, CD34, Ki67, S100, estrogen, and progesterone receptors. Histological and immunohistochemical findings as well as clinical characteristics were then correlated with progression-free interval and overall survival. There were four homologous and five heterologous carcinosarcomas. Five patients had early stage disease. Seven of the patients were optimally debulked. All patients were treated with anthracycline-based chemotherapy following surgery. With regard to immunohistochemistry, all specimens were negative for CD34, c-erbB-2, estrogen, and progesterone receptor expression. Five tumors overexpressed p53 and four specimens demonstrated a positive staining for Ki67. Reactivity for VEGF and CD45RO was observed in four and two tumor specimens, respectively. The median overall survival was 32.9 months with no statistical difference between early and advanced stages, while median time to progression was 13.5 months. p53 overexpression demonstrated a trend for better overall survival. Only p53 overexpression seems to influence overall survival although, due to the small number of patients studied, no safe conclusions can be drawn. Despite the predominance of early stage patients that favorably influenced overall survival, aggressive surgical cytoreduction followed by anthracycline-based treatment were the cornerstone in our multimodality approach. © 2004 Elsevier Inc. All rights reserved.

Docetaxel is an effective agent for the treatment of androgen-independent prostate cancer (AIPC). Its combination with estramustine phosphate (EMP) has shown promising results in AIPC but the toxicity remains considerable. In an effort to minimize toxicity, we designed an every-2-week docetaxel administration regimen with a 3-day low-dose EMP regimen. Patients with bone metastases also received zoledronic acid. A total of 54 patients with AIPC received docetaxel at 45 mg/m2 and EMP (140 mg orally every 8 hours for nine doses) every 2 weeks. Zoledronic acid was administered at 4 mg every 28 days. Of the 49 assessable patients, 22 (45%, 95% confidence interval [CI] 31% to 60%) had a prostate-specific antigen response. Of 24 patients with measurable disease, 9 (38%, 95% CI 19% to 59%) had a response to therapy (one complete response and eight partial responses). The median time to progression was 4.4 months (95% CI 2.7 to 6), and overall survival was 13.3 months (95% CI 9 to 17.6). Toxicity was mild, with only 5 cases of grade 3 or 4 toxicity. The pain score improved by 1 point in 21 (54%) of 39 symptomatic patients, and 14 (40%) of 38 patients who used analgesics discontinued analgesic consumption by the end of treatment. The combination of an every-2-week regimen of docetaxel, EMP, and zoledronic acid is an effective, well-tolerated regimen that results in symptomatic improvement in a significant proportion of patients with AIPC. © 2005 Elsevier Inc.

A small percentage of germ cell tumors is known to be familial. There are several reports describing familial cases of testicular germ cell tumors; however, there are only a few of them reporting germ cell tumors that occurred in both males and females of the same family. We present a family with three children, two females and one male, previously healthy, who all developed germ cell malignancies. The first sibling was diagnosed with malignant teratoma of the ovary, the second one with dysgerminoma involving both ovaries, and the male one with both embryonal carcinoma and seminoma of the testicle. Our case report suggests that the possibility of an association between germ cell tumors of both ovaries and testis should be considered. © 2004 Elsevier Inc. All rights reserved.

Waldenström's macroglobulinemia (WM) is a lymphoplasmacytic lymphoma which produces monoclonal immunoglobulin M (IgM). Over the last decade, new treatment modalites have been developed for the management of this disorder. Our objective is to provide treatment recommendations for WM. A review of published reports was facilitated by a MEDLINE computer search and by a manual search of Index Medicus. Other sources included abstracts and conference proceedings. Most patients with WM who are diagnosed by chance without symptoms should not be treated. Initiation of treatment should not be based on level of serum monoclonal protein per se. The presence of cytopenia, significant adenopathy or organomegaly, symptomatic hyperviscosity, severe neuropathy or cryoglobulinemia indicates the need for treatment. The main choices for primary treatment of symptomatic patients with WM include alkylating agents, the nucleoside analogs fludarabine or cladribine and the monoclonal antibody rituximab or combinations of these programs. There are no data from prospective randomized studies to recommend the use of one program over another. Nevertheless, the need for rapid disease control may favor the use of nucleoside analogs, whereas the presence of significant cytopenia may favor rituximab. High dose therapy with autologous stem cell transplantation may induce responses even in patients with resistance to all three class of agents. It may be prudent to avoid nucleoside analogs in patients who are candidates for high dose therapy. Despite the lack of randomized trials, a rational approach to the treatment of patients with WM is possible. Several factors, including the presence of cytopenias, need for rapid disease control, candidacy for autologous stem cell transplantation, age and co-morbid conditions, should be taken into consideration when choosing the most appropriate primary treatment.

Background: The majority of patients with advanced urothelial cancer are elderly, but data regarding this specific age group are limited. We compared the tolerability and efficacy of first-line platinum (cisplatin or carboplatin)-based chemotherapy in elderly patients (≥70 years) with those in younger patients. Patients and methods: A total of 381 patients with advanced urothelial carcinoma received CIMV (cisplatin, ifosphamide, methotrexate, vinblastine) (n=32), MVAC (methotrexate, vinblastine, doxorubicin, cisplatin) (n=105), DC (docetaxel, cisplatin) (n=174), CaG (carboplatin, gemcitabine) (n=64) or other regimes (n=6) and were included in this analysis. Results: A total of 116 patients were ≥70 years. Elderly patients experienced more frequent neutropenia grade 3/4 (55% versus 37%, P=0.087) and renal toxicity (28% versus 10%, P=0.033) among patients treated with CIMV/MVAC, and neutropenic infections (4% versus 0%, P=0.019) among patients treated with DC. Median survival did not differ significantly between elderly and younger patients (9.3 versus 10.5 months, P=0.16). Eastern Cooperative Oncology Group performance status (PS) and haemoglobin were independently associated with prognosis. Patients with PS <2 and haemoglobin ≥10g/dl had a median survival of 14 months as opposed to 5 months for patients with PS ≥2 or haemoglobin <10g/dl (P <0.001). Conclusion: Elderly patients with advanced urothelial cancer tolerate platinum-based chemotherapy well and derive the same benefit as their younger counterparts. © 2005 European Society for Medical Oncology.

Thalidomide has antiangiogenic and immunomodulatory properties and has recently been used in the management of human malignancies. Multiple studies have confirmed its activity in multiple myeloma, alone or combined with dexamethasone and/or chemotherapy as first- or second-line treatment. In addition, it may reduce the need for transfusions in patients with myelofibrosis or myelodysplastic syndromes. The activity of thalidomide in solid tumours is less prominent. The most promising results have been reported in Kaposi's sarcoma, malignant melanoma and prostate cancer, especially when it is combined with chemotherapy. Recently, thalidomide analogues (immunomodulatory drugs), with higher immunomodulatory activity and different toxicity profile, have been developed. They have already shown promising activity in multiple myeloma and are currently being evaluated in clinical studies. © 2005 Ashley Publications Ltd.

This is a retrospective analysis of 150 patients with advanced non-small cell lung cancer who had failed prior treatment or were unfit for chemotherapy and were treated with oral gefitinib ('lressa', ZD1839; AstraZeneca) 250 mg/day. Thirty-two patients who received gefitinib for 3 weeks or less were not included in the analysis. For the remaining 118 evaluable patients, the mean age was 63.1 years; most patients had received prior chemotherapy (97.5%), Eastern Cooperative Oncology Group performance status scores 0-2 (97.4%) and stage IV disease (64.4%). The majority were symptomatic (84.6%). Disease control was observed in 30 patients (25.4%), of whom five had a partial response and 25 had stable disease; 18 (15.3%) were not evaluable. Median duration of treatment was 29.9 weeks in responding patients and 11.5 in patients with progressive disease (p<0.0001). Median overall survival was 7.3 months (15.2 months for disease control) and median progression-free survival was 3.2 months. Gefitinib was well tolerated, with grade 3/4 skin rash and diarrhea seen in 2.5 and 4.2% of patients, respectively. Clinical benefit was evaluated using questionnaires before and following treatment with gefitinib. In 82 patients with completed questionnaires, evaluation revealed symptom improvement in 40.1% and improvement in general feeling in 31.4%. Epidermal growth factor receptor (EGFR) analysis found that efficacy did not correlate with tumor EGFR overexpression. Therefore, in this retrospective analysis, gefitinib treatment provided disease control in 25% of patients who derived significant palliative benefit. © 2005 Lippincott Williams & Wilkins.

Objective. Mucinous epithelial ovarian cancer (mEOC) representing about 10% of all EOC are known to be possibly resistant to platinum-based chemotherapy and bear a poorer prognosis with respect to other subtypes of EOC. This study was undertaken to compare response and survival to platinum-based chemotherapy between patients with advanced stages III and IV mEOC and serous EOC (sEOC). Methods. A retrospective analysis was performed in 47 patients with advanced stage of mEOC treated with first-line platinum-based chemotherapy in the context of several study protocols of the Hellenic Cooperative Oncology Group (HeCOG) between 6/7/1983 and 25/2/2003. The outcome was compared to that of 94 patients with sEOC treated with the same protocols during the same study period (ratio mucinous: serous 1:2). Results. One hundred forty-one patients (47 stages III and IV mEOC, 94 stages III and IV sEOC) treated with platinum-based chemotherapy were analyzed. The overall response rate for mEOC was 38.5% (complete remission 18%) (95% CI 23.4-55.4%) and 70% (complete remission 47%) (95% CI 58.5-80.3%) for sEOC (P = 0.001). After a median follow-up of 77.8 months, median survival and time to tumor progression (TTP) were not significantly different between the two groups (33.2 months [95% CI 23.3-43.1 months] vs. 38.0 months [95% CI 26.8-49.2 months], P = 0.46, 11.8 months [95% CI 7.2-16.4 months] vs. 20.0 months [95% CI 15.7-24.2 months], P = 0.18, respectively). Conclusion. Patients with mEOC have significantly lower response to first-line platinum-based chemotherapy compared to patients with sEOC. This low response to platinum-based chemotherapy was not translated in inferior TTP or survival. Our data indicate that a new strategy for chemotherapy in mEOC should be adopted, one that focuses on new agents without cross-resistance to platinum agents. © 2005 Elsevier Inc. All rights reserved.

Background: The potential role of the adult thymus in T-cell homeostasis subsequent to lymphopenia remains the subject of debate. We examined whether thymic activity contributes to reconstitution of the peripheral T-cell pool, a critical process for patients recovering from antineoplastic therapy. Methods: In selected patients with various neoplastic diseases we assessed peripheral blood lymphocyte subsets by flow-cytometry, including thymus-derived, CD4+ T cells expressing the CD45RA molecule, and thymic size rebound by CT scan before, and 3, 6 and 12 months after completion of cytotoxic therapy. Results: Adult patients (n = 21, mean age of 30 years, range 18-49) had higher baseline numbers of B and lower numbers of NK cells than elderly patients (n = 15, mean age of 79 years, range 70-91), while total T-cell numbers did not differ. Despite the reduction of lymphocyte counts being comparable in the adult (mean of 45%) and elderly (mean of 49%) groups, occurring at, or near, completion of treatment, an enlargement of the previously atrophic thymus was evident in 63% of the adult, but in none of the elderly, subjects. In 22 patients who remained active disease-free during the following year, B cells and NK cells recovered to pretreatment levels as soon as at 3 months, whereas overall T-cell recovery occurred at 6 months post-treatment. Thymic rebound, observed in 11 of 22 patients who were of younger age, correlated significantly with a faster and more complete recovery of CD45RA+ CD4+ (mainly helper-naïve) T cells. Conclusion: The adult thymus appears capable of regeneration, at least up to middle age, contributing significantly to the reconstitution of the peripheral T-cell pool following chemotherapy-induced lymphopenia. In advanced age, however, although peripheral homeostatic pathways appear intact, regeneration of the naïve repertoire is incomplete. © 2005 Blackwell Publishing Ltd.

Aim: The aim of the present study was to correlate bcl-2 protein expression and DNA-ploidy status with established prognostic parameters in renal cell carcinoma (RCC) and to examine their impact on disease progression and patient survival. Methods: Both parameters were prospectively measured in 50 consecutive radical nephrectomy specimens using flow cytometry. They were correlated with the tumor grade, stage and histological type. Kaplan-Meier survival analysis for all parameters was performed. Results: Bcl-2 protein expression was higher in RCC compared to normal renal tissue (P < 0.0001). Aneuploid tumors had higher bcl-2 expression compared to diploid tumors (P = 0.015). Bcl-2 expression and DNA content were not correlated with tumor histological types (P = 0.277/ P = 0.419), grades (P = 0.690/P = 0.449), T categories (P = 0.637/P = 0.585) or stages (P = 0.726/ P = 0.800). Median follow-up time was 46 months (range, 5-84) with a mean overall survival of 61.8 months (95% confidence interval, 53.7-69.9). Tumor stage was the only statistically important prognostic factor (P = 0.0045). Conclusion: Although Bcl-2 expression was correlated with tumor DNA content, the prognostic value of these two parameters following radical nephrectomy was not established.

In most cases multiple myeloma is an incurable plasma cell malignancy. Despite the use of conventional therapy or high-dose chemotherapy with autologous stem cell transplantation (ASCT), patients continue to relapse at a constant rate. A small minority of patients are cured by allogeneic transplantation. Novel drugs targeting not only the myeloma cell but also its interactions with the malignant microenvironment have recently been used in patients with relapsed/refractory disease. So far, ASCT has been the treatment of choice for eligible myeloma patients. However, many questions regarding the management of myeloma patients remain unanswered. How safe is ASCT in elderly patients? Is there a role for non-myeloablative allogeneic transplantation in multiple myeloma? What is the role of novel agents, such as thalidomide, its analogues and bortezomib, in the treatment of newly diagnosed patients or as maintenance post-ASCT? This review summarises all available data for the current treatment options for myeloma providing a useful algorithm for its management. © 2005 Ashley Publications Ltd.

Background: A phase II study was conducted to evaluate the efficacy and toxicity of the combination of gemcitabine (GEM) and pegylated liposomal doxorubicin (PLD) in patients with platinum- and/or taxane-resistant/refractory advanced epithelial ovarian cancer (AEOC). Patients and Methods: Patients (pts), who had been treated with platinum or paclitaxel and met the criteria of resistant/refractory AEOC, received GEM 650 mg/m2 days 1 and 8 and PLD 25 mg/m2 day 1 every 4 weeks up to a total of 6 cycles, unless disease progression or adverse effects prohibited further therapy. Results: Thirty-seven patients entered the study. There was 1 complete (3%) and 7 partial responses (19%) for an overall response rate of 22%. Two patients had stable disease (5.5%). After a median follow-up of 16.2 months, the median survival was 8.4 months and time to treatment failure 2.7 months. The most frequent severe toxicity was myelosuppression recorded in 13 (35%) patients. Severe stomatitis was recorded in only 2 (5%) cases and severe palmar-plantar erythrodysesthesia in 1 patient. One severe allergic reaction (grade 4) to PLD was recorded following the third cycle of treatment. Conclusion: The combination of GEM and PLD in patients with AEOC, who are resistant/refractory to platinum and/or Taxanes, did not show any superiority over monotherapy. However, in view of the acceptable toxicity profile, the above combination may deserve further investigation in a randomised setting.

Background: Irinotecan (IRI) and oxaliplatin (OXA) are effective in the treatment of colorectal cancer. Previously untreated patients with advanced colorectal carcinoma (CRC) were randomly assigned to receive IRI plus leucovorin (LV)/5-fluorouracil (5-FU), or OXA plus LV/5-FU in order to compare the response rates, time-to-tumor progression, overall survival rates, and toxicity profiles of these two agents. Materials and methods: From January 1999 to February 2002, 295 patients were randomized to receive either IRI/LV/5-FU or OXA/LV/5-FU. The treatment schedules consisted of weekly IRI 70 mg/m2 or OXA 45 mg/m2 plus LV 200 mg/m2 followed immediately by intravenous bolus 5-FU 450 mg/m2 for 6 weeks, followed by a 2-week rest period. Treatment was continued for up to four cycles or until disease progression, unacceptable toxicity or patient refusal. Results: There were no significant differences between the study arms in the overall response rate (33% with IRI/LV/5-FU versus 32% with OXA/LV/5-FU based on responses demonstrated on a single evaluation; 23% with IRI/LV/5-FU versus 22.3% with OXA/LV/5-FU based on responses confirmed according to WHO criteria) median time to progression (8.9 versus 7.6 months), and median overall survival (17.6 versus 17.4 months). Toxicity profiles (grades 3 and 4) were similar in the IRI and OXA arms (diarrhea 12.3% and 9.8%, neutropenia 8.2% and 4.9%, and febrile neutropenia 1.4% and 1.4%, respectively), with the exception of grade 3 sensory neuropathy, which almost exclusively occurred in the OXA arm (0% versus 5.6%; P = 0.003, Fisher's exact test). Conclusion: The IRI/LV/5-FU and OXA/LV/5-FU regimens demonstrated equally substantial efficacies and manageable toxicity profiles in the first-line treatment of patients with advanced CRC. However, IRI/LV/5-FU may be the preferable regimen to avoid significant neurotoxicity associated with OXA-LV/5-FU. © 2005 European Society for Medical Oncology.

The purpose of this retrospective study, the largest unselected series in our country, was to illustrate the clinicopathological features of non-Hodgkin's lymphoma (NHL) classified according to the World Health Organization (WHO) classification of lymphoid neoplasms. A retrospective analysis was conducted and clinical features of histological subtypes were established in 810 patients (age ≥ 15 years) with NHL who were treated at 8 major centers representative of Greece. There were 435 males and 375 females 95% of them aged >30 years. B symptoms were present in 34% of the patients, while 45.3% had stages I-II and 54.6% had stages III-IV. LDH was increased in 37% of the patients. B cell lymphomas formed 88% of the cases whereas T cell lymphomas formed 12% of the total. Indolent lymphomas accounted for 31.1%, aggressive ones for 66.7% and very aggressive ones for 2.4% of all NHLs. Among indolent lymphomas extranodal ones (MALT B cell lymphoma) were the most common subset while follicular lymphoma grade I and II and small lymphocytic ones presented with equal frequency. Among the aggressive lymphomas diffuse large cell lymphoma (DLCL) was the most common subtype; this entity along with large-cell immunoblastic lymphomas accounted for 45.2% of all B cell lymphomas. Among the T cell lymphomas, peripheral T cell lymphomas and anaplastic large cell lymphomas of the T/null-cell type were the most common subtypes. The most common extranodal presentation was the gastrointestinal tract (GI). Next in frequency were primary extranodal NHL of the head and neck region. MALT B cell lymphomas were found in almost half of the patients with GI tract NHL, whereas in all other extranodal places DLCL was the predominant histological subtype. The median survival for indolent and aggressive NHL was 123.5 and 55.5 months, respectively. This is the first report of a large series of malignant lymphomas in Greece using the WHO classification. It appears that there are no significant differences between NHL in Greece and other large series as far as clinical and extranodal presentation is concerned. The frequency of follicular lymphoma in the current study is comparable to that reported from Asian countries and mainland Europe, but lower than that of US and Northern European series. There were no important differences in the incidence of the remaining histological subtypes between Greece and other European countries. Copyright © 2005 S. Karger AG.

BACKGROUND. Oral-based antibiotic therapy is the standard of care in the management of cancer patients with low-risk neutropenic fever. Nevertheless, to the authors' knowledge, the best antibiotic regimen and the feasibility of ambulatory treatment have not been clearly defined. METHODS. The authors evaluated the efficacy and safety of moxifloxacin as outpatient treatment in cancer patients with febrile neutropenia who were selected according to the recently proposed Multinational Association for Supportive Care in Cancer (MASCC) risk assessment model. Moxifloxacin was given at a dose of 400 mg orally once daily. RESULTS. Fifty-four patients with solid and hematologic malignancies, the majority of whom (84%) had advanced disease, were included in the current study. The median neutrophil count at the time of study entry was 340/mm3 (range, 20-950/mm3) and the median duration of neutropenia was 4 days (range, 3-14 days). Of 55 neutropenic episodes, 50 (91%) had a successful outcome with a median time to defervescence of 2 days (range, 1-5 days). A multivariate analysis indicated that severe neutropenia (an absolute neutrophil count of < 100 mm3) was the only independent factor associated with treatment failure (P < 0.04). Moxifloxacin was found to be well tolerated and there were no infectious deaths reported. CONCLUSIONS. The results of the current study demonstrated that moxifloxacin was a highly effective and safe regimen in the outpatient treatment of cancer patients with febrile neutropenia. © 2005 American Cancer Society.

Background: We compared the combination plus Carboplatin plus paclitaxel, which is considered the treatment of choice for initial chemotherapy of advanced ovarian cancer (AOC) with a regimen combining alternating carboplatin and cisplatin plus paclitaxel. The two platinum derivatives have been previously combined as they are not totally cross-resistant and as they share no overlapping toxicities. Patients and methods: Patients with AOC, after the initial cytoreductive surgery were randomized to either 6 courses of paclitaxel at 175 mg/m2 as 3h infusion plus Carboplatin at 7 AUC (Arm A) or Paclitaxel at the same dose plus Carboplatin again at 7 AUC for cycles 1,3,5, while for cycles 2,4,6 Cisplatin at 75 mg/m2 substituted for Carboplatin (Arm B). Results: 247 patients are analyzed. Significant differences were not found, both in terms of PFS (38 vs 39 months, p=0.95) and overall survival (40.6 vs 38.6 months, p=0.79). There was not also difference in 5-year survival rate (35% vs 39%) or 5-year PFS rate (23% vs 28%). Age >60, PS 2, stage IV disease and presence of residual disease were adversely related to the overall survival. Conclusion: Both regimens are well tolerated and effective. Alternating cisplatin with carboplatin does not improve the results compared with the standard combination. © 2005 European Society fr Medical Oncology.

Rituximab is an active agent for the treatment of Waldenström's macroglobulinemia. However, many patients do not respond to this agent and several others develop secondary resistance. In order to identify clinical and laboratory parameters that could predict a higher likelihood for response, we evaluated 54 patients who were treated with single-agent rituximab. Twenty-four patients (44%)exhibited ≥ 50% reduction of serum monoclonal protein. Previously untreated and pretreated patients had the same probability for response. Low response rates were noted in patients with serum monoclonal protein level ≥ 40 g/L (17%) and serum albumin level < 35 g/L (14%). Furthermore, a multivariate analysis indicated that high serum monoclonal protein and low albumin were the dominant variables associated with shorter time to progression. The presence of 2, 1, or none of these variables was associated with median times to progression of 4 months, 11 months, and approximately 48 months, respectively. We conclude that patients with low levels of monoclonal protein and normal albumin are the best candidates for treatment with rituximab.

Background: Brain metastases from epithelial ovarian cancer (EOC) are rare. A retrospective study of all patients diagnosed with brain metastases from EOC over the last 20 years, according to the Hellenic Cooperative Oncology Group (HeCOG) tumor registry, was conducted. Patients and Methods: A total of 1450 patients with EOC were treated within various HeCOG protocols from 1983 to 2004. Seventeen (1.17%) of them developed brain metastases. Results: The median age at diagnosis of brain metastases was 58 years (range, 24 to 77). At initial diagnosis, 2 patients had stage II, 12 had stage III and 3 had stage IV disease. Serous papillary adenocarcinoma was the most common histological subtype [12 patients (71%)]. All patients had received initial cisplatin-based chemotherapy. The median time from initial diagnosis to central nervous system (CNS) relapse was 15.9 months (range, 1.4 to 70.8). The CNS was the only site of disease in 13 (76.5%) patients, whereas 4 (23.5%) patients had additional extracranial disease. Two (12%) patients with isolated single brain lesions underwent surgical excision of the metastases, followed by whole brain radiation therapy (WBRT) and chemotherapy. Four (24%) patients were treated with WBRT alone, 6 (35%) patients with WBRT plus chemotherapy and 2 (12%) had only supportive care, while 3 (18%) patients decided not to have any further treatment after the diagnosis of brain metastases. The median survival time from diagnosis of CNS relapse was 5.7 months (range, 0.2 to 22.6) and the median survival time from diagnosis of EOC was 27.4 months (range, 3.0 to 71.4). In patients with CNS recurrence as the only site of disease, the median survival time from diagnosis of CNS relapse was 5.3 months (range, 0.6 to 22.6) and in those with both CNS and extracranial disease, the median survival time was 3.9 months (range, 0.2 to 11.9) (p=0.5597). There was a statistically significant difference in survival for those treated with WBRT plus chemotherapy (10.0 months) versus those treated with WBRT alone (1.5 months) and those who had only supportive care (0.2 months) (p=0.0003). Conclusion: The incidence of cerebral metastases in our patients with EOC was 1.17%, which is consistent with the mean value of all series reported in the literature. The prognosis of patients with brain metastases from EOC is poor. Patients who had WBRT and chemotherapy fared better than those who received WBRT alone.

To investigate the efficacy and toxicity of the combination of gemcitabine and vinorelbine in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBL), 22 patients with relapsed or refractory DLBL were treated with gemcitabine 1000 mg/m2 and vinorelbine 30 mg/m2 on days 1 and 8 every 3 wk for a maximum of six cycles. Fourteen patients were considered chemosensitive while eight patients were considered chemoresistant to the last treatment regimen. All 22 patients were assessed for response to treatment. Three patients (14%) achieved complete remission and eight patients (36%) had partial remission of their disease, with an overall response rate of 50%. With a median follow up of 44 months, the median time to progression (TTP) for all patients was 8.1 months while the median overall survival (OS) was 12.9 months. Toxicity was minimal and all patients were treated on an outpatient basis. The combination of gemcitabine and vinorelbine is an effective and well-tolerated regimen for patients with relapsed of refractory DLBL. © Blackwell Munksgaard 2005.

Objectives. To evaluate the safety profile and therapeutic value of the combination of estramustine, mitoxantrone, and vinorelbine in the treatment of hormone-refractory prostate cancer. Methods. Fifty-two patients with hormone-refractory prostate cancer were included in the study. Median age was 70 years (range, 49 to 100 years), World Health Organization performance status ranged from 0 to 2. The treatment schedule consisted of estramustine capsules (140 mg 3 times daily on days 1 to 3 and days 8 to 10 per os), intravenous mitoxantrone (12 mg/m2 on day 2), and intravenous vinorelbine (25 mg/m2 on day 2 and day 9), given in a 3-week cycle. Results. Thirty-one percent of patients with measurable soft-tissue disease demonstrated an objective response, which included six complete and ten partial responses in all involved organs (bone responses not included). Twenty-nine patients (56%) had a greater than 50% reduction in serum prostate-specific antigen level. The median duration of response was 6.9 months, and the median survival for all patients was 14.5 months. Conclusions. The combination of estramustine, vinorelbine, and mitoxantrone is safe, well tolerated, and relatively active in patients with hormone-refractory prostate cancer. © 2005 Elsevier Inc.

Purpose of investigation: Late relapses are infrequent in ovarian cancer. We present the characteristics and outcome of patients who relapsed at least five years after first-line chemotherapy. Methods: Six cases were retrieved from 203 patients treated from 1994 to 1998. Results: Time to recurrence ranged from five to nine years. The initial stage was I or II in all cases, while histology was: endometrioid (4 cases), clear cell (1 case) and unspecified adenocarcinoma (1 case). Only two of five assessable patients responded to chemotherapy. Compared to earlier relapses, late relapses were characterized by earlier stages (p < 0.001), non serous histology (p = 0.010) and absence of symptoms (0% vs 46.5%, p = 0.025) at baseline. Five of 16 relapses (31%) among patients with Stage I or II were late relapses. Conclusion: Late relapses of ovarian cancer occur in early stages, where they are relatively frequent, while the chemosensitivity of the disease may be less than expected.

The purpose of this retrospective study was to illustrate the clinicopathological features of patients presenting with multifocal extranodal non-Hodgkin lymphoma (NHL). Among 810 patients with NHL, 37 cases (4.2%) were found to have multiple extranodal involvement (two or more sites). There were 24 men and 13 women, with a median age of 63 years. The majority of these cases (n = 26) had gastric or intestinal (GI) involvement with or without other extranodal sites. Lung along with another extranodal site was relatively common in the present series. Stratification of the 37 cases according to the International Prognostic Index (IPI) showed that 89% of the patients belonged to the high-risk groups. Diffuse large-B -cell lymphoma (DLBCL) accounted for 62%, and mucosa-associated lymphoma tissue (MALT) lymphoma accounted for 27% of all cases. After induction treatment with anthracycline-based regimens, complete remission was achieved in 21 patients (57%), partial remission was achieved in six patients (16%), and seven patients (19%) had no response, while three patients (8%) were nonevaluable. In conclusion, multifocal extranodal NHL is a heterogeneous group of diseases. The majority of them arise at various sites in the GI tract. DLBCL was the most frequent histological subtype followed by MALT lymphoma. Risk group, as defined by the IPI, was predictive of survival. ©AlphaMed Press.

Objectives: Purpose of this study was to compare prognostic factors and outcome of patients with multiple myeloma (MM) aged > 70 yr at diagnosis with those of younger patients. We also applied the recently proposed International Staging System (ISS) for MM in these patients. Patients and methods: Among 1,162 newly diagnosed, symptomatic MM patients included in our database, 357 (31%) were > 70 yr of age. Clinical and laboratory variables were evaluated in patients > 70 yr and in younger patients and were assessed for possible correlation with survival in patients > 70 yr of age. Results: Most clinical and laboratory features were similar in the two groups of patients but older patients presented more frequently with advanced ISS (P = 0.02). Despite similar response rates to primary treatment, younger patients survived longer than patients > 70 yr of age (40 vs. 28 months, P = 0.001). There was a longer survival of younger patients than that of older patients diagnosed with ISS stage 1 (median 71 vs. 54 months, P = 0.007) and ISS stage-2 patients (median: 38 vs. 26 months, P = 0.0008) but for patients with ISS stage 3 median survival was similarly poor in the younger and older age group (21 and 20 months, P = 0.283). Other variables associated with impaired prognosis were severe anemia, extensive bone marrow plasmacytosis and elevated serum LDH. Conclusions: Older patients with MM present more often with advanced ISS and have significantly shorter survival than younger patients. The ISS retained its prognostic significance within the group of elderly patients. © Blackwell Munksgaard 2005.

Bone disease is a major feature of multiple myeloma. Myeloma-induced bone destruction is the result of an increased activity of osteoclasts, which is not accompanied by a comparable increase of osteoblast function. Recent studies have revealed that new molecules such as the receptor activator of nuclear factor-kappa B (RANK), its ligand (RANKL), osteoprotegerin (OPG), and macrophage inflammatory protein-1α are implicated in osteoclast activation and differentiation, while proteins such as dickkopf-1 inhibit osteoblastic bone formation. These new molecules seem to interfere not only with the biology of myeloma bone destruction but also with tumour growth and survival, creating novel targets for the development of new antimyeloma treatment. Currently, bisphosphonates play a major role in the management of myeloma bone disease. Clodronate, pamidronate and zoledronic acid are the most effective bisphosphonates in symptomatic myeloma patients. Biochemical markers of bone remodeling have been used in an attempt to identify patients more likely to benefit from early treatment with bisphosphonates. Furthermore, using microarray techniques, myeloma patients may be subdivided into molecular subgroups with certain clinical characteristics, such as propensity for lytic lesions that may need early prophylactic treatment. Recent phase I studies with recombinant OPG and monoclonal antibodies to RANKL appear promising. © 2005 European Society for Medical Oncology.

The irinotecan-cisplatin combination has emerged as a new standard for the treatment of advanced-stage small-cell lung cancer (AS-SCLC). To move forward we developed a 3-day regimen of cisplatin, etoposide and irinotecan. Successive cohorts of AS-SCLC patients were treated with irinotecan administered as a single 1-h infusion in combination with fixed doses of cisplatin (20 mg/m 2) and etoposide (75 mg/m2), both given for three consecutive days (ECI regimen). Irinotecan dose was escalated from 60 mg/m 2 by 40-mg/m2 increments. At mid-step between the maximum tolerated dose (MTD) and the previous dose level, patients were randomized for the day of administration of irinotecan (day 1 vs day 3). A total of 36 AS-SCLC patients received 166 courses of treatment at four dose levels. The MTD of irinotecan was 140 mg/m2 (three dose-limiting toxicities, DLTs), and the recommended optimal dose (ROD) 120 mg/m2 (two DLTs). DLTs were febrile neutropenia and grade 3 diarrhea. Other toxicities were mild. No difference in toxicity was seen between the two time schedules. A 77% (95% CI 63.25-90.75%) response rate was recorded among 31 evaluable patients and the median survival was 12 months. The ECI regimen was well tolerated and showed considerable activity in patients with AS-SCLC. Phase II/III evaluation is ongoing. © Springer-Verlag 2005.

Purpose: The aim of this study was to explore the effect of dose-dense sequential chemotherapy with or without paclitaxel primarily on disease-free survival (DFS) and secondarily on overall survival (OS) in patients with high-risk operable breast cancer. Patients and methods: From June 1997 until November 2000, 604 patients with T1-3N1M0 or T3 N0M0 tumors were randomized to three cycles of epirubicin 110 mg/m2 followed by three cycles of paclitaxel 250 mg/m2 followed by three cycles of 'intensified' CMF (cyclophosphamide 840 mg/m2, methotrexate 47 mg/m2 and fluorouracil 840 mg/m2) (group A), or to four cycles of epirubicin followed by four cycles of CMF, as in group A (group B). All cycles were given every 2 weeks with granulocyte colony-stimulating factor support. Results: A total of 595 patients were eligible. Median follow-up was 61.7 months for group A and 62 months for group B. The 3-year DFS was 80% in group A and 77% in group B. Survival rates were 93% and 90%, respectively. The effect of treatment on the hazard of death was different according to hormonal receptor status. More specifically, in patients with negative receptor status the hazard of death was significantly higher for group B (hazard ratio 2.42). Both regimens were well tolerated and severe acute side-effects were infrequent. No cases of severe cardiotoxicity or acute leukemia were recorded. Conclusions: The present study failed to demonstrate a significant difference in DFS or OS between the two treatment groups. However, our study has shown clearly that high-dose paclitaxel can be safely incorporated to dose-dense sequential chemotherapy. © 2005 European Society for Medical Oncology.

Purpose of investigation: Uterine papillary serous carcinoma (UPSC) and uterine clear cell carcinoma (UCCC) represent more aggressive tumors than the more common endometroid cancers, exhibiting a propensity for distant metastasis. The aim of this study was to investigate the activity and safety of paclitaxel/carboplatin chemotherapy as the only adjuvant treatment in patients with surgically resected UPSC and UCCC. Methods: Fifteen patients with Stage IB-IV UPSC or UCCC were treated with a mean of six courses of paclitaxel 175 mg/m3 plus carboplatin AUC 5 at three-week intervals, three to six weeks after undergoing surgery with curative intent. No patient had residual disease after surgery and none underwent pre- or post-chemotherapy irradiation. Results: With a median follow-up of 29.4 months, six patients (40%) relapsed and two (13%) died of disease. Mean time to recurrence was 16.9 months. Recurrence rate per Stage was 17% for Stage IB/C, 57% for Stage IIIA/C and 50% for Stage IV. Projected 5-year overall survival and progression-free survival was 79.7% and 55.7%, respectively. All relapses were abdominopelvic whereas in one case pelvic recurrence was accompanied by lung metastasis. The most frequent grade 3-4 toxicity was neutropenia. Conclusion: Chemotherapy with paclitaxel plus carboplatin is feasible and possibly prevents distant metastasis when used as adjuvant in UPSC and UCCC.

The aim of this study was the evaluation of the effect of intermediate doses of thalidomide with dexamethasone (Thal/Dex) on disease course and bone disease in patients with refractory/relapsed myeloma who were under zoledronic acid therapy. We studied 35 patients, who received thalidomide at a dose of 200mg/daily. We measured, pre-, 3 and 6 months post-treatment soluble receptor activator of nuclear factor-κB ligand (sRANKL), osteoprotegerin (OPG), osteopontin (OPN), markers of bone resorption and formation. Before treatment, patients had increased levels of sRANKL/OPG ratio, bone resorption markers and OPN, while they had suppressed bone formation. The pretreatment sRANKL/OPG ratio correlated with the extent of bone disease. Thal/Dex administration resulted in a significant reduction of sRANKL/OPG ratio, and bone resorption. Bone formation, OPG and OPN did not show any alteration. Changes of sRANKL/OPG ratio correlated with changes of bone resorption markers. Thal/Dex was given for a median time of 10 months and the median follow-up period was 22 months. The response rate was 65.7%. The median survival was 19.5 months. β2-microglobulin, type of response and International Staging System predicted for survival. These results suggest that the combination of intermediate dose of Thal/Dex is effective in patients with refractory/relapsed myeloma and improves abnormal bone remodeling through the reduction of sRANKL/OPG ratio. © 2005 Nature Publishing Group. All rights reserved.

This study determined the role of the combined use of 99mTc- sestamibi and 99mTc-pentavalent dimercaptosuccinic acid (V-DMSA) scintigraphy in evaluating the effectiveness of chemotherapy in patients with multiple myeloma. Methods: In 20 patients with multiple myeloma who had received or were receiving chemotherapy, 99mTc-sestamibi and 99mTc-V-DMSA scanning was performed to evaluate the effectiveness of chemotherapy. Results: In group A (11 patients with active disease), 42 99mTc-sestamibi-positive lesions were found. Thirty-seven of those lesions were also positive for 99mTc-V-DMSA uptake, as were 16 additional lesions (nonactive) (NAL). Thus, in group A, the total number of positive lesions (TPL) detected was 58 and the NAL/TPL ratio was 16:58. In group B (9 patients in remission), 5 99mTc-sestamibi-positive lesions were found. A further 22 lesions were also positive for 99mTc-V-DMSA uptake. Thus, in group B, the NAL/TPL ratio was 22:27. Therefore, the NAL/TPL ratios considered to represent effectively treated lesions were 27.6% and 81.5% for groups A and B, respectively. Conclusion: Combined use of the 2 agents allows the effectiveness of chemotherapy to be evaluated through a comparison of NAL and TPL multiple myeloma lesions even in the absence of a baseline study.

Purpose: To review the diagnostic criteria, prognostic factors, response criteria, and treatment options of patients with Waldenstrom's macroglobulinemia (WM). Methods: A review of published reports was facilitated by the use of a MEDLINE computer search and by manual search of the Index Medicus. Results: WM should be regarded as a distinct clinicopathologic entity and confined to those patients with lymphoplasmacytoid lymphoma who have demonstrable serum immunoglobulin M monoclonal protein. Treatment decisions should rely on specific clinical and laboratory criteria. Initiation of therapy should not be based on serum monoclonal protein levels per se. The three main choices for systemic primary treatment of symptomatic patients with WM include alkylating agents (chlorambucil), nucleoside analogs (fludarabine and cladribine), and the monoclonal antibody rituximab. There are no data from prospective randomized studies to recommend the use of one first-line agent over another, although consideration of a patient's candidacy for autologous stem-cell transplantation (ASCT) should be taken into account to avoid stem cell-damaging agents. There are preliminary data to suggest that combinations of nucleoside analogs and alkylating agents with or without rituximab may improve response rates at the expense of higher toxicity. Conclusion: WM is a distinct low-grade lymphoproliferative disorder. When therapy is indicated, alkylating agents, nucleoside analogs, and rituximab are reasonable choices. Several factors, including the presence of cytopenias, need for rapid disease control, candidacy for ASCT, age, and comorbidities, should be taken into consideration when choosing the most appropriate primary treatment. © 2005 by American Society of Clinical Oncology.

Purpose: To quantitate the individual levels of melphalan-induced DNA damage formation and repair in vivo and to search for possible correlations with clinical outcome in patients with multiple myeloma (MM). Patients and Methods: The formation and subsequent repair of DNA damage (monoadducts and interstrand cross-links) in the p53 tumor-suppressor gene, the proto-oncogene N-ras, and the house-keeping gene beta-actin during the first 24 hours after treatment with high-dose melphalan (HDM; 200 mg/m2) supported by autologous blood stem-cell transplantation (ABSCT) was measured in blood leukocytes of 26 patients with MM. The peak DNA adduct levels, the total amount of adducts over time, and the rate of adducts repair in each gene were correlated with response and time to progression after HDM. Results: The levels of gene-specific DNA damage formation and the individual repairing capacity varied up to 16-fold among patients, indicating that the melphalan-induced biologic effect in vivo is highly individualized. A significantly greater DNA damage and a slower rate of repair in p53 for all end points under study were found in patients who achieved tumor reduction compared with nonresponding patients. Furthermore, longer progression-free survival correlated with increased peak monoadduct levels in the p53 gene (P = .032). Conclusion: Increased DNA damage and slower repairing capacity in the p53gene from blood leukocytes after HDM correlate with improved outcome of patients with MM who undergo ABSCT. These results suggest that quantitation of such biologic end points may identify patients who are more likely to benefit from this procedure. © 2005 by American Society of Clinical Oncology.

Purpose: Osteonecrosis of the jaw (ONJ) has been associated recently with the use of pamidronate and zoledronic acid. We studied the incidence, characteristics, and risk factors for the development of ONJ among patients treated with bisphosphonates for bone metastases. Patients and Methods: ONJ was assessed prospectively since July 2003. The first bisphosphonate treatment among patients with ONJ was administered in 1997. Two hundred fifty-two patients who received bisphosphonates since January 1997 were included in this analysis. Results: Seventeen patients (6.7%) developed ONJ: 11 of 111 (9.9%) with multiple myeloma, two of 70 (2.9%) with breast cancer, three of 46 (6.5%) with prostate cancer, and one of 25 (4%) with other neoplasms (P = .289). The median number of treatment cycles and time of exposure to bisphosphonates were 35 infusions and 39.3 months for patients with ONJ compared with 15 infusions (P < .001) and 19 months (P = .001), respectively, for patients with no ONJ. The incidence of ONJ increased with time to exposure from 1.5% among patients treated for 4 to 12 months to 7.7% for treatment of 37 to 48 months. The cumulative hazard was significantly higher with zoledronic acid compared with pamidronate alone or pamidronate and zoledronic acid sequentially (P < .001). All but two patients with ONJ had a history of dental procedures within the last year or use of dentures. Conclusion: The use of bisphosphonates seems to be associated with the development of ONJ. Length of exposure seems to be the most important risk factor for this complication. The type of bisphosphonate may play a role and previous dental procedures may be a precipitating factor. © 2005 by American Society of Clinical Oncology.

Background. Data about the outcome and prognostic factors in the group of patients with non-squamous cell advanced or recurrent carcinomas of the uterine cervix are limited. We compared the outcome of patients with non-squamous with that of squamous cell carcinomas after platinum-based combination chemotherapy as first line therapy for stage IV or recurrent cervical carcinoma. Patients and methods. A total of 200 patients with stage IV or recurrent carcinomas of the cervix received platinum-based combination chemotherapy and were included in our analysis. Results. There were 58 patients with non-squamous and 142 patients with squamous cell carcinomas. Response to chemotherapy was 53.5% in non-squamous vs. 43.5% in squamous carcinomas. Histology was not an independent predictor of tumor response (P = 0.797). Response rates were lower in patients with relapse only in a previously irradiated area in both squamous (26.9% vs. 53.5%, P = 0.005) and non-squamous carcinomas (47.1% vs. 65%, P = 0.270). Weight loss was the only significant predictor of survival in non-squamous histology patients (P <0.0001). There was no significant difference in median survival between squamous (11.57 months [95% CI 9.35-13.79]) and non-squamous carcinomas (19.05 months [95% CI 13.63-24.47]) (P = 0.064). After adjustment for independent prognostic factors (ECOG performance status and weight loss), differences in survival remained not significant. Conclusion. Our study showed a similar outcome for both squamous and non-squamous stage IV or recurrent cervical carcinomas treated with platinum-based combination chemotherapy. © 2005 Elsevier Inc. All rights reserved.

Background: Magnetic resonance imaging (MRI) has been a useful technique for the assessment of patients with multiple myeloma (MM). We evaluated the prognostic significance of different MRI patterns in symptomatic patients with MM. Patients and methods: A total of 142 symptomatic MM patients underwent MRI before treatment. MRI patterns of involvement were correlated with known prognostic variables, including the International Staging System (ISS), response to treatment and survival. Results: Focal marrow lesions were identified in 50% of patients, diffuse marrow replacement in 28%, a variegated pattern in 14% and normal pattern in 8%. When patients with the diffuse pattern were compared with patients with the other MRI patterns, they had features of more advanced disease such as higher ISS, anemia, hypercalcemia, elevated lactate dehydrogenase and extensive marrow plasmacytosis. Response rate was similar among patients with different MRI patterns. Median survival was 24 months for patients with the diffuse pattern, 51 months for those with the focal pattern, 52 months for those with the variegated pattern and 56 months for patients with the normal pattern (P = 0.001). The presence or absence of a diffuse MRI pattern separated patients with ISS stages I and II into two subgroups with significantly different survival times of 28 months and 61 months, respectively (P = 0.01). Furthermore, a diffuse MRI pattern predicted inferior outcome regardless of whether or not patients had received high-dose therapy with autologous stem cell transplantation. Conclusion: Diffuse marrow replacement on MRI adds to the evaluation of patients with multiple myeloma and their management. © 2005 European Society for Medical Oncology.

Purpose: p27 protein is regarded as a valuable prognostic biomarker in cancer with a potential use as a molecular target. However, different methods of immunohistochemical assessment have yielded conflicting results. Here, we sought to determine the prognostic value of p27 in ovarian cancer using a novel method of compartmentalized in situ protein analysis. Experimental Design: A tissue array composed of 150 advanced stage ovarian cancers uniformly treated, with surgical debulking followed by platinum-paclitaxel combination chemotherapy, was constructed. For evaluation of p27 protein expression, we used an immunofluorescence-based method of automated in situ quantitative measurement of protein analysis [automated quantitative analysis (AQUA)]. Results: The mean follow-up time of the patients was 34.3 months. Patients with low Fédération Internationale des Gynaecologistes et Obstetristes stage were more likely to have low nuclear p27 expression (P = 0.008). Low nuclear p27 expression was associated with improved 3-year overall survival (66% versus 20%, P = 0.0047) and disease-free survival (27% versus 12%, P = 0.022). In multivariable analysis, adjusting for well-characterized prognostic variables, low nuclear p27 expression level was the most significant prognostic factor for both disease-free and overall survival. Conclusions: Our results indicate that quantitative assessment of nuclear p27 expression level by automated in situ quantitative analysis is a strong predictor for outcome in ovarian cancer. © 2005 American Association for Cancer Research.

Background and Objectives. Bortezomib is a selective proteasome inhibitor which has shown significant activity in a variety of hematologic malignancies including multiple myeloma, mantle cell lymphoma and marginal zone lymphoma. Thus, this agent is worth studying in patients with Waldenström's macroglobulinemia (WM). Design and Methods. Patients with refractory or relapsed WM were treated with bortezomib administered intravenously at a dose of 1.3 mg/m2 on days 1, 4, 8 and 11 in a 21-day cycle for a total of four cycles. Results. Ten previously treated patients with WM were treated with bortezomib. Most patients had been exposed to all active agents for WM and eight patients had received three or more regimens. Six of these patients achieved a partial response which occurred at a median of 1 month. The median time to progression in the responding patients is expected to exceed 11 months. Bortezomib was relatively well tolerated. The more common toxicities were mild or moderate thrombocytopenia, fever and fatigue while peripheral neuropathy occurred in three patients and one patient developed severe paralytic ileus. Interpretation and Conclusions. Our preliminary data indicate that bortezomib is an active agent in patients with heavily pretreated relapsed/refractory WM. Four cycles of this agent may be adequate to assess sensitivity in this disease. Further studies are needed to confirm our results and to evaluate combinations of bortezomib with other active agents. ©2005 Ferrata Storti Foundation.

Background: Several lines of laboratory evidence support the epidermal growth factor receptor (EGFR) as an adverse prognostic indicator in ovarian cancers. However, different methods of immunohistochemical assessment have yielded conflicting results. Here, we sought to determine the prognostic value of EGFR in ovarian cancer using a novel method of compartmentalized in situ protein analysis. Methods: A tissue array composed of 150 advanced-stage ovarian cancers uniformly treated, with surgical debulking followed by platinum-paclitaxel combination chemotherapy, was constructed. For evaluation of EGFR protein expression, we used an immunofluorescence-based method of automated in situ quantitative measurement of protein analysis (AQUA). Results: Mean follow-up time for the entire cohort was 34.4 months. Eighty-one of 150 cases had sufficient tissue for AQUA analysis. High tumor EGFR expression was associated with poor outcome for overall survival (P = 0.0001) and disease-free survival (P = 0.0005) at 3 years. In multivariable analysis, adjusting for well-characterized prognostic variables, EGFR expression status was the most significant prognostic factor for disease-free and overall survival. Conclusion: The conflicting results in the literature regarding the prognostic value of EGFR may be due to the technical difficulties inherent in assessing EGFR with immunocytochemistry. In the present study, we show that measurement of EGFR protein levels in ovarian cancer using AQUA is feasible and can give important prognostic information. © 2005 American Association for Cancer Research.

The role of neoadjuvant chemotherapy in muscle-invasive bladder cancer has been clarified by recent randomized studies and meta-analyses, which all showed that cisplatin-based, combination chemotherapy offers a significant survival advantage. Preoperative chemotherapy results in downstaging in a significant percentage of patients, which is an independent factor of favorable prognosis. Nevertheless, the optimal sequence of perioperative chemotherapy remains undefined. The authors examine the results of large Phase II and randomized studies as well as the role of neoadjuvant chemotherapy in the context of bladder preservation strategies. Finally, issues of improving therapeutic efficacy and directing clinical research are discussed. © 2005 Future Drugs Ltd.

The diagnosis of Waldenström's macroglobulinemia (WM) requires evidence of bone-marrow infiltration by lymphoplasmacytoid lymphoma and detection of serum monoclonal protein of IgM type. The normal counterpart of the WM malignant cell is believed to be a postgerminal-center B cell. The clinical manifestations and laboratory abnormalities associated with WM are related to direct tumor infiltration and to the amount and specific properties of IgM. Asymptomatic patients should be followed without treatment. When treatment is indicated, the three main choices for systemic frontline treatment are chlorambucil, the nucleoside analogues fludarabine or cladribine and the monoclonal antibody rituximab. There is evidence that high-dose therapy with autologous stem-cell transplantation is effective even in patients with advanced and resistant disease. Patient's age, hemoglobin and serum β2-microglobulin before treatment are important prognostic variables which correlate with survival. © 2005 Elsevier Ltd. All rights reserved.

Objectives. To evaluate prospectively the combination of a luteinizing hormone-releasing hormone analog with a somatostatin analog and dexamethasone in patients with hormone-refractory prostate cancer (HRPC) in a randomized Phase II study. HRPC presents a challenging therapeutic problem. Salvage chemotherapy is the usual approach at this stage of the disease. The combination of a luteinizing hormone-releasing hormone analog with a somatostatin analog and dexamethasone has produced objective clinical responses in HRPC. Methods. Forty patients with HRPC were randomized to receive one of two treatments. Group 1 underwent chemotherapy (estramustine 140 mg three times daily and etoposide 100 mg orally for 21 days) and group 2 the combination of a somatostatin analog (lanreotide 30 mg intramuscularly every 14 days) and dexamethasone (4 mg tapered to 1 mg), in addition to androgen ablation by orchiectomy or a luteinizing hormone-releasing hormone analog (triptorelin 3.75 mg intramuscularly every 28 days). The clinical and prostate-specific antigen (PSA) response, overall survival, time to progression, and toxicity were compared between the two groups. Results. The data of 20 patients in group 1 and 18 in group 2 were analyzed. The demographic and clinical data were similar in the two groups at study entry. A PSA response (decrease of greater than 50%) was observed in 45% of group 1 and 44% of group 2. The difference was not statistically significant. A partial clinical response was observed in 29% and 30% of groups 1 and 2, respectively. Again, the difference was not statistically significant. Changes in performance status and pain score during treatment were not significantly different in the two groups. Hematologic toxicity was more frequent in group 1 (80% of patients), and mild diabetes was more frequent in group 2 (22% of patients). The overall survival was 18.8 months in group 1 and 18 months in group 2 (not statistically significant). The time to progression was 6 versus 4 months and, in the PSA responder subgroup, it was 8 versus 7.7 months in groups 1 and 2, respectively (neither difference was statistically significant). Conclusions. The results of our randomized Phase II study indicated that the new combination treatment (luteinizing hormone-releasing hormone analog, somatostatin analog, and dexamethasone) may be equally effective as salvage chemotherapy in patients with HRPC in terms of the clinical and PSA response, overall survival, and time to progression. A larger prospective Phase III trial is required to confirm our observations. © 2004 Elsevier Inc.

Thalidomide-based regimens (TBR) are now widely used for the treatment of refractory multiple myeloma and have shown significant activity in newly diagnosed patients. In some patients with secretory disease, we observed discrepancies between the reduction of the monoclonal protein levels and the plasma cell infiltration in the bone marrow and/or extramedullary sites of relapse after treatment with TBR. The purpose of this study was to assess the incidence and analysis of this phenomenon in all myeloma patients treated with TBR in our Institution. Patients and methods: We studied all patients who received TBRs and had a follow up time of at least 6 months. Partial response (PR) was defined as at least 50% reduction of serum myeloma protein and soft tissue plasmacytomas and/or > 90% reduction of Bence Jones protein excretion and minor response as a > 25% reduction of the serum myeloma protein or > 50% reduction of the Bence Jones myeloma protein. Results: Between July 1999 and July 2002 we treated 94 patients with advanced myeloma and 9 patients with newly diagnosed disease with TBR. Sixty-seven patients (66%) achieved either partial or minor response. In 4 patients (3 with advanced and 1 with newly diagnosed myeloma) the bone marrow was heavily infiltrated by plasma cells, despite a decrease of the paraprotein levels ranging from 38% to 68%. This discordance between monoclonal protein levels and bone marrow plasmacytosis was noted in 6% of patients rated as responders and in 11% of responding patients who actually had a repeat bone marrow assessment. Furthermore 6 responding patients, after achieving a PR which lasted between 5 and 9 months, relapsed with bone marrow (all cases), and extramedullary (2 cases) plasmacytosis, without increase of serum and/or urine monoclonal protein. This hyposecretory conversion was noted in 12.5% of relapsing patients. Conclusion: Our data indicate that after treatment with TBR some patients with myeloma show discordant responses of the monoclonal protein levels and the bone marrow or extramedullary plasmacytosis. If our data are confirmed, they may have practical implications for assessment of response and follow up of patients treated with TBR.

Background: High-dose chemotherapy with autologous stem cell transplantation after initial cytoreductive chemotherapy with the combination vincristine, doxorubicin and dexamethasone (VAD) is considered an effective therapy for many patients with newly diagnosed, symptomatic multiple myeloma. Response to initial cytoreductive chemotherapy is important for the long-term outcome of such patients. Thalidomide has recently shown significant antimyeloma activity. We studied the efficacy and toxicity of the combination of a liposomal doxorubicin-containing VAD regimen with thalidomide, administered on an outpatient basis, as initial cytoreductive treatment in previously untreated patients with symptomatic myeloma. Patients and methods: Thirty-nine myeloma patients were treated with vincristine 2 mg intravenously (i.v.), liposomal doxorubicin 40 mg/m2 i.v. administered as single dose on day 1, and dexamethasone 40 mg per os daily for 4 days. Dexamethasone was also given on days 15-18 of the first cycle of treatment. The regimen was administered every 4 weeks for four courses. Thalidomide was given daily at a dose of 200 mg at bedtime. Response to treatment was evaluated after four cycles of treatment. After completion of four cycles, the patients were allowed to proceed to high-dose chemotherapy or to receive two additional cycles of the same treatment. Results: On an intention-to-treat basis, 29 of the 39 patients (74%) responded to treatment. Four patients (10%) achieved complete and 25 (64%) partial response. Three patients (8%) showed minor response and seven (18%) were rated as non-responders. Major grade 3 or 4 toxicities consisted of neutropenia (15%), thrombocytopenia (15%), deep vein thrombosis (10%), constipation (10%), skin rash (5%) and peripheral neuropathy (5%). Two patients (5%) experienced early death due to infection. Conclusions: The combination of vincristine, liposomal doxorubicin, and dexamethasone (VAD doxil) with thalidomide is an effective and relatively well-tolerated initial cytoreductive treatment.Prospective randomized studies are required in order to assess the effect of this regimen on the long-term outcome of patients with multiple myeloma.

Purpose: To evaluate the prognostic significance of the immunohistochemical expression of p53, bcl-2, c-erbB-2 and cathepsin-D in epithelial ovarian cancer (EOC). Methods: We analyzed 100 patients with ovarian carcinoma, FIGO Stage IC-IV who underwent primary cytoreductive surgery and received adjuvant chemotherapy with cyclophosphamide and a platinum analogue (CP) (n = 46) or paclitaxel and a platinum analogue (TP) (n = 54). Immunohistochemical expression was studied on paraffin-embedded tissue from the primary tumor. Results: After a median follow-up of 55 months median progression-free survival (PFS) and overall survival (OS) were 16 and 41 months, respectively. Positive bcl-2 staining and absence of cathepsin-D expression were associated with an increased complete response rate in the CP group (p = 0.011 and p = 0.003) but not in the TP group. PFS and OS were not associated with the expression of any of the markers studied. FIGO stage (p = 0.006) and histology (p = 0.047) were the only independent prognostic factors for survival. Conclusion: Bcl2 and cathepsin D expression are associated with response to CP but not TP chemotherapy. P53, bcl-2, c-erb B-2 and cathepsin D expression was not correlated with PFS and OS in our study.

Objective. Patients with epithelial ovarian cancer (EOC) who relapse more than 6 months following completion of platinum-based primary chemotherapy are considered platinum-sensitive, and can be effectively retreated with cisplatin or carboplatin. The nucleoside analogue gemcitabine has proven activity in both platinum-sensitive and platinum-resistant disease. We conducted a phase II study using the combination of carboplatin and gemcitabine for the treatment of patients with relapsed platinum-sensitive and paclitaxel-pretreated EOC. Methods. Forty-three patients were treated with gemcitabine 1000 mg/m 2, intravenously, over 30 min on days 1 and 8, and carboplatin at AUC 5 on day 1. Courses were administered every 3 weeks on an outpatient basis. Results. Among 37 patients with measurable or evaluable disease, 15 (40.5%) achieved an objective response including 10 complete and 5 partial responses. The median overall survival was 24.5 months, and the median time to progression for all patients was 9 months. The treatment was well tolerated without toxic deaths; the most common toxicities were Grade 3 or 4 neutropenia, anemia, and thrombocytopenia that occurred in 69%, 26%, and 24% of patients, respectively. Conclusions. The combination of carboplatin and gemcitabine is a well-tolerated outpatient regimen with activity in patients with relapsed platinum-sensitive and paclitaxel-pretreated EOC. However, a randomized prospective study is justified to define whether the addition of gemcitabine to single-agent carboplatin results in improved efficacy in this subset of patients. © 2003 Elsevier Inc. All rights reserved.

Purpose: Radical cystectomy represents the treatment of choice for muscle infiltrative bladder carcinoma. Adjuvant chemotherapy has been used to improve outcome after cystectomy. We report results in a prospective cohort of patients at high risk for relapse who were treated with the combination of paclitaxel and carboplatin as adjuvant treatment following cystectomy for muscle invasive bladder cancer. Materials and Methods: A total of 92 patients with extravesical tumor extension (pT 3b or greater) or lymph node involvement (N+) were treated with 4 cycles of paclitaxel at 175 mg/m2 and carboplatin (area under the curve 5 according to the Calvert formula) every 3 weeks following radical cystectomy. Patients were followed every 6 months thereafter. Results: Median followup was 36.6 months. Chemotherapy was well tolerated with 62% of patients receiving 100% of the expected chemotherapy doses without delays. Grade 3 or 4 neutropenia was reported in 19% of patients, while neutropenic fever was reported in 7%. Five-year overall, cause specific and disease-free survival was 28.9% (95% CI 14.8 to 43.0), 36.6% (95% CI 24.4 to 49.7) and 29% (95% CI 16.3 to 42.4), respectively. Conclusions: Adjuvant chemotherapy with paclitaxel and carboplatin is feasible and could be used as adjuvant treatment for high risk bladder carcinoma. Its true value should be assessed in prospective, randomized trials.

Objectives To evaluate, in a multicenter Phase II study, the safety and efficacy of the combination of gemcitabine and carboplatin, as first-line treatment in elderly and unfit patients with advanced bladder carcinoma. The toxicity of platinum-based chemotherapy combinations represents a common problem for elderly or unfit patients with advanced bladder carcinoma. Methods Patients with previously untreated inoperable or metastatic bladder carcinoma and an Eastern Cooperative Oncology Group performance status greater than 2, age older than 75 years, or creatinine clearance of less than 50 mL/min were treated with carboplatin area under the curve 4 on day 1 and gemcitabine 1000 mg/m 2 on days 1 and 8, every 21 days for a total of six cycles. Results A total of 56 patients (48 men and 8 women, median age 75 years) were enrolled. Of these patients, 46% had a performance status of 2 to 3, 68% had a creatinine clearance of less than 50 mL/min, and 59% had distant metastases. The overall response rate was 36% (95% confidence interval 23.4% to 49.6%), and an additional 14 patients had disease stabilization (25%, 95% confidence interval 14.4% to 38.4%). The median time to progression was 4.8 months, the median overall survival was 7.2 months, and the 1-year survival rate was 26%. Grade 3 or 4 toxicity included anemia (18%); thrombocytopenia (16%); neutropenia (27%), with two episodes of febrile neutropenia requiring hospitalization; diarrhea (2%); and fatigue (5.5%). Two toxic deaths occurred during the study. Conclusions The combination of gemcitabine and carboplatin has some activity as first-line treatment of advanced bladder carcinoma in the elderly and those unfit for cisplatin-based chemotherapy, with manageable toxicity, and represents a reasonable choice for the treatment of such patients. © 2004 Elsevier Inc.

Objective: We conducted a phase II trial to evaluate the activity of oral letrozole in women with relapsed or recurrent epithelial ovarian cancer. Methods: Twenty-seven patients were treated with letrozole at a dose of 2.5 mg once a day. Patients with measurable or evaluable disease (n = 21) and those with only increasing CA 125 serum levels (n = 6) were eligible. Paraffin-fixed histological sections from tumor specimens resected at the initial laparotomy were assessed for the presence of estrogen, and progesterone receptors. Results: Among the 21 patients with measurable or evaluable disease who were evaluated for response by WHO criteria, we observed one complete and two partial responses for an objective response rate of 15%. Using criteria for CA 125 response we obtained a marker response in 4 of 27 patients (15%), and the marker remained stable in 5 additional patients (18%). Letrozole treatment was generally well tolerated. No correlation was observed between tumor marker response or stabilization and either estrogen or progesterone receptor expression. Conclusion: The results of our study suggest that the aromatase inhibitor letrozole is an agent with some activity and limited toxicity for relapsed ovarian cancer. As we could not find any association between response and hormonal receptor expression, the underlying mechanisms of letrozole action have to be elucidated. Copyright © 2004 S. Karger AG, Basel.

Several studies have indicated that age, hemoglobin and serum albumin are among the most important prognostic factors for survival of patients with Waldenstrom's macroglobulinemia (WM). Furthermore, recent data indicate that serum b2-microglobulin may be also significant. The recently proposed International Staging System (ISS) for multiple myeloma is based on serum albumin and b2-microglobulin. We designed a study to assess this model in patients with WM. Our analysis included 83 previously untreated patients with WM who required systemic treatment and in whom pretreatment values for both serum albumin and b2-microglobulin were available. Based on these variables the patients were stratified into three ISS stages. Stage I: albumin ≥ 3.5 g/dl and b2-microglobulin < 3.5 mg/dl, stage II: albumin < 3.5 g/dl and b2-microglobulin < 3.5 mg/gl or b2-microglobulin 3.5 - 5.5 mg/dl and stage III: b2-microglobulin > 5.5 mg/dl. Low albumin (3.5 g/dl) and high b2-microglobulin (≥ 3.5 mg/dl) were recorded in 45% and 52% of patients respectively. The distribution of patients in the three ISS stages was: stage I: 30%, stage II: 43% and stage III: 27%. The median overall survival from the date of treatment initiation was 115 months. The median survival according to ISS was not reached for stage I, 116 months for stage II and 54 months for stage III (P = 0.02). Our analysis indicated that the recently proposed ISS for multiple myeloma could stratify the patients with WM into three distinct subgroups with significantly different survival times. If this model is validated in independent series, it could provide a new staging system for WM based on readily available and reproducible variables. © 2004 Taylor & Francis Ltd.

A phase I pharmacokinetics and dose-finding study and a phase II study of the combination of pegylated liposomal doxorubicin HCI (PLD) and paclitaxel were conducted in patients with recurrent or metastatic head and neck cancer (HNC). Sixty patients with recurrent or metastatic disease were enrolled in the study: 11 patients in the phase I study and 49 patients in the phase II study. In the phase I study, the initial dose level of PLD was 35 mg/m2 as a 1-h infusion with escalating increments of 5 mg/m2 until the maximum tolerated dose (MTD) was reached. A fixed dose of paclitaxel (175 mg/m 2) was administered as a 3-h infusion. The combination was administered every 28 days. Pharmacokinetic studies performed on 10 patients indicated that the sequence of drug administration did not cause clinically significant modifications in the pharmacokinetics of either drug. The MTD for PLD was 45 mg/m2 (dose level 3) and the dose-limiting toxicity was febrile neutropenia, occurring in three of five patients. The phase II dose of PLD was 40 mg/m2 (dose level 2) and a total of 214 cycles were delivered. Grade 3 or 4 neutropenia was observed in 26% patients and febrile neutropenia occurred in 16% of patients. Grade 3 palmar-plantar erythrodysesthesia (PPE) was recorded in only one patient. The overall response rate was 28% for patients with non-nasopharyngeal tumors [95% confidence interval (CI) 15-45%] and 28.6% for the study population (95% CI 17-43%). The median survival for the study population was 9.7 months; 1-year survival was 38%. We conclude that the recommended dose for the combination of PLD and paclitaxel is 40 and 175 mg/m2 every 28 days, without granulocyte colony stimulating factor support. The combination of paclitaxel with PLD demonstrated activity in recurrent or metastatic HNC, a favorable toxicity profile and relative ease of administration. © 2004 Lippincott Williams & Wilkins.

Primary mediastinal B-cell lymphoma (PMBCL) is a discrete subset of large B-cell lymphoma with unique clinicopathologic features. The question of optimal treatment emerges because it is an uncommon but not rare occurrence. A retrospective study was therefore conducted in a group of patients in Greece to evaluate the clinical features and treatment outcome in this disease. Twenty patients with PMBCL, with a median age of 42 years, treated at centers participating in the Hellenic Cooperative Oncology Group over the last 20 years, were reviewed. Thirteen (65%) had bulky disease at the time of presentation, 7 (35%) had superior vena cavae obstruction, and 15 (75%) had extranodal involvement. All received doxorubicin-containing chemotherapy, followed in 11 cases by mediastinal radiotherapy. With a median follow-up of 91 months, the median survival is 67.7 months. These data are consistent with those reported from other centers concerning the patient's characteristics, natural history, response pattern to chemoradiation therapy, and prognosis. Response to therapy proved of prognostic significance. A key question that remains is the prompt identification of patients who would benefit from innovative or more intensive therapies.

Background: Small series and retrospective studies have suggested that treatment with gemcitabine may be associated with pulmonary toxicity. However, a prospective evaluation of cancer patients treated with gemcitabine-based chemotherapy without neoplastic involvement of the thorax and without administration of radiotherapy has not been performed. Patients and methods: To investigate this issue, 41 consecutive patients receiving gemcitabine and carboplatin underwent prospective evaluation of lung function, which included pulmonary symptoms, pulmonary function tests, arterial blood gases and radiographic studies. Assessment was performed before and after completion of chemotherapy in all patients. Patients with a substantial decline in diffusion capacity for carbon monoxide (DLCO), defined as a drop of ≥20%, were reassessed 2 months later. Results: After chemotherapy, there were no significant changes in forced vital capacity (FVQ, forced expiratory volume in 1 s (FEV1), FEV1/FVC ratio, alveolar volume or total lung capacity. In contrast, there was a significant decline in DLCO (73 ± 22 versus 67 ± 24% predicted; P = 0.017) and in carbon monoxide transfer coefficient (KCO) (89 ± 24 versus 80 ± 24% predicted; P = 0.004). Arterial blood gases did not change following treatment. Ten of the 41 patients (24%) exhibited a substantial decline in DLCO, which, however, recovered within 2 months (DLCO at baseline, immediately after therapy and at 2 months after completion of treatment, 84 ± 14, 58 ± 16 and 77 ± 17% predicted, respectively; P < 0.001; baseline DLCO versus DLCO at 2 months, P > 0.05). Four of the 41 patients (10%) experienced dyspnea, which was self-limiting, with the exception of one patient who developed interstitial lung fibrosis. Among the various risk factors examined, older age, female gender and lower baseline DLCO were associated with more profound changes in DLCO post-treatment. Conclusions: This prospective analysis showed that the combination of gemcitabine and carboplatin induces a significant, but reversible, decrease in diffusion capacity, which is mostly asymptomatic. Thus, this regimen is safe as regards clinically significant lung toxicity. © 2004 European Society for Medical Oncology.

Introduction: Thalidomide is an oral agent with significant activity in one-third of patients with refractory myeloma. However, long-term continuous administration of thalidomide can be associated with significant side effects such as deep-vein thrombosis and peripheral neuropathy. Furthermore, it is not clear whether continuous administration of thalidomide is necessary for its antimyeloma effect. We performed a phase II study with a combination that was based on the intermittent administration of thalidomide. Materials and methods: A total of 53 patients with previously treated myeloma received cyclophosphamide 150 mg/m2 p.o. every 12 h before meals on days 1-5, thalidomide 400 mg p.o. in the evening on days 1-5 and 14-18 and dexamethasone 20 mg/m2 in the morning after breakfast on days 1-5 and 14-18 (CTD). The CTD combination was repeated every 28 days for three courses. Subsequently, responding patients were scheduled to receive maintenance treatment with monthly courses of CTD administered only for the first five days of each month. Results: On an intention-to-treat basis, 32 patients (60%) achieved a partial response with a median time to response of 1.5 months. Among the 43 thalidomide-naïve patients, 67% responded. Toxicities were mild or moderate and the cumulative incidence of deep-vein thrombosis and peripheral neuropathy was 4 and 2%, respectively. The median time to progression for responding patients was 12 months and the median overall survival for all patients was 17.5 months. Conclusion: The oral, outpatient pulsed CTD regimen is associated with significant activity in patients with previously treated multiple myeloma. The incidence of deep-vein thrombosis and peripheral neuropathy appears to be lower than expected when thalidomide is being administered on a continuous basis. © 2004 The European Hematology Association. All rights reserved.

The aim of this study was to evaluate the role of markers of bone remodelling, and osteoclast activation/function in patients with monoclonal gammopathy of undetermined significance (MGUS). We have measured serum levels of soluble RANKL (sRANKL), osteoprotegerin (OPG), macrophage inflammatory protein-1alpha (MIP-1α), markers of bone resorption [N-telopeptide of collagen type-I (NTX), and tartrate-resistant acid phosphatase isoform-5b (TRACP-Sb)] and bone formation [bone-alkaline phosphatase (bALP)] in 40 MGUS patients. These parameters were compared with those of 42 newly diagnosed myeloma patients, and 45 healthy, gender- and age-matched controls. MGUS patients had elevated levels of NTX, sRANKL, and sRANKL/OPG ratio compared with controls (P < 0.0001). Furthermore, TRACP-5b, MIP-1α and NTX were decreased in patients with MGUS compared with myeloma patients (P < 0.001), while OPG and bALP were increased (P < 0.001). Serum levels of MIP-1α, as well as TRACP-Sb, and sRANKL/OPG ratio were reduced, while bALP was increased in MGUS patients, even when compared with myeloma patients who had stage I/II disease. These results demonstrate that increased osteoclastogenesis leading to increased bone resorption is present in MGUS but seems to be compensated for by normal bone formation, which is absent in MM. Furthermore MIP-1α, bALP, and sRANKL/OPG may be useful tools for distinguishing between cases of MGUS and early myeloma.

Thalidomide, an oral agent with antiangiogenic and immunomodulatory properties, is being investigated extensively in the management of advanced cancer. Multiple studies with large numbers of patients have confirmed that this drug has significant activity in multiple myeloma. Some patients with myelofibrosis or myeodysplatic syndromes may reduce their need for transfusions after thalidomide treatment. The activity of thalidomide in solid tumors is less prominent. Studies in Kaposi's sarcoma, malignant melanoma, renal cell carcinoma and prostate cancer appear more promising especially when thalidomide is combined with biological agents or with chemotherapy. Limited activity was demonstrated in patients with glioma, while thalidomide appears to be inactive in patients with head and neck cancer, breast or ovarian cancer. © 2004 European Society for Medical Oncology.

Thalidomide, a glutamic acid derivative, was withdrawn from clinical use in 1962 due to its severe teratogenic effects. Its recent reinstitution in clinical practice was related to its benefits in leprosy and multiple myeloma. Moreover, the antiangiogenic and immunomodulatory properties of thalidomide have led to its evaluation in several malignant diseases, including myelofibrosis, renal cell cancer, prostate cancer, and Kaposi sarcoma. However, thalidomide use is associated with several side effects: somnolence and constipation are the most common, while deep vein thrombosis and peripheral neuropathy are the most serious. A combination of thalidomide with steroids or chemotherapy is being evaluated in several phase 2 studies. While it is not yet clear whether these combinations will enhance efficacy, they appear to increase the toxicity of thalidomide, and thalidomide analogs are being developed to minimize this toxicity. Ongoing studies will clarify the potential advantages of these agents in the treatment of neoplastic diseases. © 2004 by Elsevier Inc.

Patients with soft tissue sarcoma (STS), even after complete local disease control, often relapse locally or with distant metastases. This multicenter phase II study was conducted to evaluate the safety and efficacy of the combination of pegylated liposomal doxorubicin (PLD) and paclitaxel, as first-line treatment in patients with advanced STS. In all, 42 patients with locally advanced or metastatic STS, median age 54 years and median Eastern Cooperative Oncology Group performance status (PS) I were treated with PLD 45 mg m -2 and paclitaxel 150 mg m -2 every 28 days for a total of six cycles. Histological types included mainly leiomyosarcomas (43%), malignant fibrous histiocytomas (14%) and liposarcomas (12%). At study entry, 69% of patients had distant metastases, Overall response rate was 16%, including one complete (CR 2%) and six partial responses (PRs 14%), while an additional 14 patients had disease stabilization (SD 33%). At median follow-up 41.5 months, median time to progression (TTP) was 5.7 months with median overall survival (OS) 13.2 months. Grade 3-4 toxicities included neutropenia (17%), anaemia (15%), neurotoxicity (5%) and palmar-plantar erythrodysesthesia (9%). There were no treatment-related deaths. The combination of PLD and paclitaxel is a safe and well-tolerated regimen demonstrating modest efficacy as first-line treatment in patients with advanced STS.

Purpose: The combination of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) represents the standard regimen for inoperable or metastatic urothelial cancer, but its toxicity is significant. We previously reported a 52% response rate (RR) using a docetaxel and cisplatin (DC) combination. The toxicity of this regimen compared favorably with that reported for MVAC. We thus designed a randomized phase III trial to compare DC with MVAC. Patients and Methods: Patients with inoperable or metastatic urothelial carcinoma; adequate bone marrow, renal, liver, and cardiac function; and Eastern Cooperative Oncology Group performance status ≤ 2 were randomly assigned to receive MVAC at standard doses or docetaxel 75 mg/m2 and cisplatin 75 mg/m 2 every 3 weeks. All patients received prophylactic granulocyte colony-stimulating factor (G-CSF) support. Results: Two hundred twenty patients were randomly assigned (MVAC, 109 patients; DC, 111 patients). Treatment with MVAC resulted in superior RR (54.2% v 37.4%; P = .017), median time to progression (TTP; 9.4 v6.1 months; P = .003) and median survival (14.2 v9.3 months; P = .026). After adjusting for prognostic factors, difference in TTP remained significant (hazard ratio [HR], 1.61; P = .005), whereas survival difference was nonsignificant at the 5% level (HR, 1.31; P = .089). MVAC caused more frequent grade 3 or 4 neutropenia (35.4% v 19.2%; P = .006), thrombocytopenia (5.7% v 0.9%; P = .046), and neutropenic sepsis (11.6% v 3.8%; P = .001). Toxicity of MVAC was considerably lower than that previously reported for MVAC administered without G-CSF. Conclusion: MVAC is more effective than DC in advanced urothelial cancer. G-CSF-supported MVAC is well tolerated and could be used instead of classic MVAC as first-line treatment in advanced urothelial carcinoma. © 2004 by American Society of Clinical Oncology.

The aim of this study was to assess the effect of systemic chemotherapy on the monoclonal protein levels of patients with solid tumors who also have a monoclonal gammopathy of undetermined significance (MGUS). All patients with solid tumors who were referred to our department for consideration of systemic chemotherapy were evaluated with serum protein electrophoresis (SPEP) for the presence of MGUS. When MGUS was confirmed with immunofixation, serial SPEP was performed during and after completion of chemotherapy. Over a 6-year period, 21 patients with solid tumors and MGUS were prospectively identified and assessed. At least 50% reduction of serum monoclonal protein was noted in 4 of 11 patients treated with paclitaxel or docetaxel with a platinum analogue and in 5 of 7 patients who received an irinotecan-containing regimen. Our data indicate that in MGUS patients treated with irinotecan-containing chemotherapy regimens, a high incidence of reduction in their monoclonal protein levels is observed. Since topotecan, another topoisomerase I inhibitor, has some activity in multiple myeloma, further evaluation of irinotecan may be warranted. Evaluation of larger numbers of MGUS patients treated with chemotherapy for their underlying malignancy may help identify "in vivo" potentially active agents and regimens for patients with overt myeloma. © Springer-Verlag 2004.

Objectives: Neoadjuvant chemotherapy has been used to improve outcome after cystectomy or for selection for bladder preservation in patients with bladder cancer. We have shown encouraging results using docetaxel and cisplatin in patients with advanced urothelial cancer. We are reporting the results of a phase II study using this combination as neoadjuvant treatment in patients with muscle invasive bladder cancer. Methods: Fifty patients were treated with docetaxel and cisplatin at 75 mg/m2 every 3 weeks for 3 cycles prior to cystectomy. Median follow-up was 70.2 months. Results: Chemotherapy was well tolerated. 5-year survival and progression-free survival (PFS) were 51.92% (95% confidence intervals [CI]: 37.76-66.08) and 52.47% (95%CI: 37.99-66.95). Multivariate analysis showed that clinical stage (cT) ≤ 3a was associated with improved 5-year survival (86.42% vs. 40.81%, p=0.027). Forty one patients underwent cystectomy. No tumor was found in 15 cases (36.6%). 5-year survival was 60.34% (95%CI: 52.2-68.48) and PFS was 57.11% (95%CI: 41.29-72.93). Absence of residual tumor was associated with improved 5-year survival (93.33% vs. 40.72%, p=0.031). Conclusions: Neoadjuvant chemotherapy with docetaxel and cisplatin is feasible and produced high pathological complete remission rate and excellent outcome in patients with no residual tumor. © 2004 Elsevier B.V. All rights reserved.

Background: To compare survival between patients with advanced breast cancer (ABC) treated with epirubicin/paclitaxel (Taxol) or paclitaxel/carboplatin (Cp) chemotherapy. Patients and methods: From January 1999 to April 2002, 327 eligible patients with ABC were randomized to receive either paclitaxel 175 mg/m2 in a 3-h infusion followed by epirubicin (EPI) 80 mg/m2 (group A) or paclitaxel, as in group A, followed by Cp at an AUC of 6 mg × min/ml (group, B) every 3 weeks for six cycles. Results: After a median follow-up of 23.5 months, median survival was not significantly different between the two groups (22.4 months versus 27.8 months, P = 0.25), whereas median time to treatment failure was significantly longer in patients treated with paclitaxel/Cp (8.1 months in group A versus 10.8 months in group B, P=0.04). Both regimens were well tolerated. In total, 39 patients (24%) in group A and 46 (29%) in group B suffered at least one severe side-effect. Quality-of-life assessment and cost analysis did not reveal any significant differences between the two groups. Conclusion: Our study suggests that the paclitaxel/Cp combination is an effective therapeutic alternative for patients with ABC in which anthracycline administration has the potential of being harmful. © 2004 European Society for Medical Oncology.

Background: Vinorelbine (VRL) has been shown to be active in hormone-refractory prostate cancer (HRPC) in phase II studies, alone or in combination. Its moderate toxicity profile is well tolerated in elderly patients. Patients and methods: Patients with metastatic prostate cancer, progressive after primary hormonal therapy, were randomised to receive intravenous VRL 30 mg/m2 on days 1 and 8 every 3 weeks, and hydrocortisone 40 mg/day or hydrocortisone alone until disease progression. Centres could choose to add aminoglutethimide 1000 mg/day to hydrocortisone as second-line hormone therapy (HT) for all their patients. Randomisation was stratified by centre. Further chemotherapy was allowed after progression. The primary end point was progression-free survival (PFS). The final analysis was performed on a total of 414 patients. Reported results were all based on intention-to-treat analyses. All progressions and responses were reviewed by an independent panel. Results: PFS was significantly prolonged in the VRL plus HT arm compared with the HT alone arm, according to the statistical hypothesis of the protocol (P=0.055 in the two-sided log-rank test with a pre-specified significance level of 10%). The 6-month PFS rates were 33.2% versus 22.8%, and the median durations of PFS were 3.7 versus 2.8 months. In the multivariate Cox analysis, which included age, Karnofsky performance status (PS), haemoglobin, alkaline phosphatase at study entry and number of prior hormonal treatments, the P value was decreased to 0.005. The prostate-specific antigen (PSA) response rate (≥50% decline sustained for at least 6 weeks) was significantly higher for VRL plus HT compared with HT (30.1% versus 19.2%; P=0.01). Clinical benefit, defined as a decrease in pain intensity or analgesic consumption or an improvement of Karnofsky PS for at least 9 weeks, and at least stable assessment in the other two, was also more frequently observed in patients who received VRL plus HT versus HT alone (30.6% and 19.2%; P=0.008). There was no statistical difference in overall survival. Forty-three per cent of patients in the HT arm received at least one line of further chemotherapy after progression, compared with 28% of patients in the VRL-based arm. Aminoglutethimide did not seem to result in better efficacy for either arm. VRL plus HT was well tolerated, with a median administered relative dose intensity of 90%; grade 4 neutropenia occurred in 6.5% of patients and non-haematological toxicity was rare. Conclusions: The combination of VRL and hydrocortisone compared with hydrocortisone alone resulted in improved clinical benefit, PFS and PSA response rate. This therapeutic gain is similar to that previously reported with mitoxantrone in combination with low-dose corticosteroids. There was no gain in survival; however, the combination is well tolerated in this elderly group of patients, who often present cardiac co-morbidities, and therefore offers an active and safe therapeutic option for patients with hormone-refractory prostate cancer. © 2004 European Society for Medical Oncology.

Ovarian germ cell tumors (OGCT) are highly curable when treated with cytoreductive surgery and platinum-based chemotherapy. We evaluated the safety and activity of a 3-day modified bleomycin, etoposide, and cisplatinum (mBEP) regimen in patients with OGCT. Patients with FIGO stages I-IV OGCT were treated with three (stages I-III complete resection) or four cycles (incomplete resection or stage IV) of bleomycin 15 mg iv, etoposide 120 mg/m 2 iv, and cisplatin 40 mg/m 2 iv for 3 days every 3 weeks. Forty-eight patients (14 with dysgerminoma and 34 with non-dysgerminomatous tumors) were included in our study. Most patients had stage I disease (65%) and complete resection of their tumor (67%). Twenty percent of patients developed grade 3 or 4 neutropenia with 4 episodes of neutropenic fever. During follow-up (median: 5 years), two patients developed progressive disease including one patient who died. All patients with stage I or II disease and all patients with dysgerminoma remain free of disease. However, 20% of patients with non-dysgerminomatous tumors stage III or IV experienced progressive disease. The modified 3-day BEP regimen was safe and effective in patients with OGCT. Further improvements are needed for patients with advanced, suboptimally debulked non-dysgerminomatous tumors. © 2004 Elsevier Inc. All rights reserved.

We evaluated the predictive value of several parameters, including the International Staging System (ISS) for myeloma, in patients with advanced disease treated with thalidomide-based regimens (TBR). We analyzed 119 patients, from 3 phase II studies. Patients with pretreatment β2 microglobulin < 3.5 mg/l and albumin ≥ 3.5 g /dl were scored ISS stage 1, patients with β2 microglobulin < 3.5 mg/1 and albumin < 3.5 g/dl or β2 microglobulin 3.5-5.5 mg/l regardless of albumin levels were scored ISS stage 2, patients with β2 microglobulin > 5.5 mg/l ISS stage 3. ISS stage was 1, 2 and 3 in 45, 32 and 23% of patients respectively. Seventy-four patients (62% achieved at least partial response. Median progression-free and overall survival were 8 months and 19.5 months respectively. ISS stage, serum LDH and performance status were independent predictive factors for survival. Based on these 3 variables a scoring system was developed with survival times of 38.1, 28.8 and 5.8 months for scores 0, 1 and 2 respectively. The ISS staging system was highly predictive for overall survival of patients with advanced myeloma treated with TBR. With the addition of performance status and serum LDH, a simple scoring system was developed which may help select patients likely to benefit from TBR. © 2004 Taylor & Francis Ltd.

Recent data have suggested that rituximab is an active agent for the treatment of Waldenstrom's macroglobulinemia (WM). However, the patients that are more likely to benefit have not been clearly defined. In order to address this question we evaluated 52 patients who were treated with single-agent rituximab in the context of prospective studies. Several clinical and laboratory variables were assessed for their correlation with response and time to progression. Twenty-three (44%) patients achieved a partial response after treatment with rituximab. Previously untreated and pretreated patients had the same probability for response. Higher response rates were noted in patients with serum monoclonal protein < 40 g/l, with serum albumin ≥ 35 g/l and with kappa light chain. The median time to progression for all patients was 13.8 months. A multivariate analysis indicated that elevated serum monoclonal protein levels and low serum albumin were the dominant variables associated with shorter progression. Presence of two, one or none of these adverse prognostic factors was associated with time to progression of 3.6 months, 11 months and more than 40 months, respectively. We conclude that rituximab is an effective treatment modality for patients with WM. Patients with both low levels of monoclonal protein and normal albumin are the best candidates for treatment with standard dose rituximab. © 2004 Taylor & Francis Ltd.

Purpose: Radical surgery represents the treatment of choice for carcinoma of the upper urinary tract. Nevertheless, approximately 50% of patients with stage T ≥ 3 or lymph node involvement die from their disease, mainly as a result of the development of distant metastases. Therefore, there is a need for effective adjuvant systemic treatment. We prospectively studied a cohort of patients who underwent surgery for high-risk carcinoma of the upper urinary tract to assess the feasibility of the combination of paclitaxel and carboplatin as adjuvant treatment. Patients and Methods: Thirty-six patients with tumor stage ≥ 3 or lymph node involvement were treated with four cycles of paclitaxel at 175 mg/m2 and carboplatin (area under the curve 5, Calvert Formula) every 3 weeks following surgery. Results: Median follow-up was 40.6 months. Chemotherapy was well tolerated with 32 patients (89%) receiving full carboplatin and paclitaxel doses without delays. The most frequent grade 3/4 toxicity was neutropenia (39%), which was complicated with fever in only one case (3%). Nonhematologic grade 3 or 4 toxicities were reported in only one case. Five-year survival was 52% (95% CI, 35% to 69%), while 5-year disease-free survival was 40.2% (95% CI, 15.8% to 64.6%). Local failure rate was 30%, as opposed to 17% of patients who developed distant metastases. No patients with grade 2 tumors relapsed during follow-up, as opposed to 60% of patients with grade 3 tumors. Conclusion: Adjuvant chemotherapy with paclitaxel and carboplatin is feasible and may reduce the risk of distant metastases in high-risk upper urinary tract carcinoma. © 2004 by American Society of Clinical Oncology.

Secondary hemophagocytic lymphohistiocytosis has been reported after infections in immunocompromised hosts or in association with several malignancies. We report a case of secondary hemophagocytic syndrome after chemotherapy for multiple myeloma, which responded dramatically to dexamethasone, etoposide, and cyclosporin A.

Background: The purpose of this study was to evaluate the role of dynamic contrast-enhanced magnetic resonance imaging (dMRI) in detecting bone marrow involvement in cancer patients. Patients and methods: We studied 50 consecutive patients with histologically confirmed malignant dissemination to the bone marrow, using dMRI of the lumbosacral spine. Time-signal intensity curves were generated from regions of interest (ROIs) obtained from areas of obvious bone marrow disease (group B). In 16 patients from group B with focal disease, ROIs were also placed on areas with apparently normal bone marrow on static magnetic resonance images (group C). Twenty-two patients with no history of malignancy were used as a control group (group A). Wash-in (WIN) and wash-out (WOUT) rates, time to peak (TTPK), time to maximum slope (TMSP) values and WIN/TMSP ratios were calculated for each patient. Mean values for the three groups were compared statistically. Six patients from group B had follow-up dMRI after chemotherapy: four patients achieved a clinical partial response and two had resistant disease. Results: A significant difference was found between groups A and B for all values. Between groups A and C, in spite of the similar static MRI appearance, all values were significantly different. Between groups B and C, a significant difference was found for WIN, WOUT rates and WIN/TMSP ratio. Follow-up dMRI data analysis correlated well with clinical staging. Conclusions: dMRI can distinguish normal from malignant bone marrow. It may identify malignant bone marrow infiltration in patients with negative static MRI and serve as both a diagnostic and prognostic tool for patients with bone marrow malignancies.

An expanded cytotoxic/memory T-cell subpopulation expressing low levels of the B-cell-specific CD20 molecule was found in peripheral blood and bone marrow of patients with multiple myeloma at the time of diagnosis, but returned to normal levels following treatment. CD3+CD20dim cells were also increased in monoclonal gammopathy of unknown significance albeit at lower levels. Lower CD3+CD20dim cell numbers at baseline may be associated with lack of response to treatment and a poor outcome. Because expansion of these T cells may be related to disease status, further studies should investigate their potentially unique function in plasma cell dyscrasias.

We report three patients with solitary bone plasmacytoma (SBP) who developed either local recurrence within the radiotherapy field or an isolated distal recurrence and who were treated with high dose therapy supported by autologous stem cell transplantation. All patients remain without evidence of disease for 4-10 years after the procedure. High dose therapy may be of value and require further study in patients with SBP who develop local or distant failure.

Treatment for Waldenstrom's macroglobulinemia (WM) has usually been reserved for symptomatic patients and has included alkylating agent-steroid combinations and, more recently, nucleoside analogues. We now describe our experience with 2-chlorodeoxyadenosine (2-CdA) alone and in combination at our center. We treated 90 consecutive, previously untreated patients with symptomatic WM using either 2-CdA alone or in combination with other agents including prednisone (pred), cyclophosphamide (Cy), and rituximab (Rit) as follows: January 1991 to December 1992 - 2-CdA 0.1 mg/kg by continuous infusion (CI) over 24 hours for days (16 patients); December 1992 to December 1995 - 2-CdA 0.1 mg/kg CI over 24 hours for 7 days plus pred 60 mg/m2 orally daily for 7 days (20 patients); July 1996 to March 1998 - 2-CdA 1.5 mg/m2 by subcutaneous injection (SC) every 8 hours for 7 days plus Cy 40 mg/m2 orally twice daily for 7 days (37 patients); August 1999 to December 2001 - 2-CdA 1.5 mg/m2 SC every 8 hours for 7 days plus Cy 40 mg/m2 orally twice daily for 7 days plus Rit 375 mg/m2 by intravenous infusion (IV) weekly for 4 weeks (17 patients). For nearly all patients, a second course was repeated after at least 6 weeks. Responding patients were monitored without further treatment until relapse. Overall response (complete [CR] + partial response [PR]) was 94% for 2-CdA alone, 60% for 2-CdA/pred, 84% for 2-CdA/Cy, and 94% for 2-CdA/Cy/Rit. Median overall survival is 73 months for 2-CdA, 41 months for 2-CdA/pred, and has not been reached for 2-CdA/Cy or 2-CdA/Cy/Rit. Cause-specific survival for 2-CdA/pred is 78 months and has not been reached for all other programs. The only poor prognostic factor for cause-specific survival was hemoglobin < 9 g/dL. 2-CdA regimens provide excellent response rates and improve cause-specific survival, with minimal treatment and little toxicity. These observations support the potential role of 2-CdA regimens as the treatment of choice for previously untreated WM. © 2003 Elsevier Inc. All rights reserved.

A study was undertaken to evaluate the frequency and natural history of disease in patients with asymptomatic Waldenstrom's macroglobulinemia (WM). Among 132 consecutive, newly diagnosed patients with monoclonal IgM, 82 (27%) had symptomatic WM indicated by anemia, lymphadenopathy, or splenomegaly. Thirtyone patients had similar clinical features but were asymptomatic and followed without therapy until disease progression. There were 19 patients with monoclonal gammopathy of undetermined significance of IgM type (MGUS). In comparison to overt WM, patients with asymptomatic WM had significantly higher hemoglobin (Hgb) level (median, 12.1 v 9.7 g/dL), lower serum β2-microglobulin (B2M) level (median, 2.4 v 3.4 mg/L), and similar IgM peaks (median, 2.2 and 1.8 g/dL). The IgM component was 3.6 g/dL or less in all patients with asymptomatic disease. For asymptomatic WM, median time to disease progression was 6.9 years with rare morbidity. Prognostic factors for early progression were Hgb < 11.5 g/dL, B2M ≥ 3.0 mg/L, and IgM peak >3.0 g/dL. Combinations of these variables defined three risk groups for progression with markedly different median times to progression of >5 years, 2 years, and 0.5 year, respectively. Response rate and survival after institution of treatment were similar to those of patients treated promptly for overt disease. We conclude that, among patients with WM, 27% were asymptomatic with slow disease progression before the need for chemotherapy. Since disease outcomes after treatment were similar to those of patients treated at diagnosis, patients with asymptomatic disease should be identified and followed without treatment for as long as risks of complications remain low. © 2003 Elsevier Inc. All rights reserved.

This presentation represents consensus recommendations for the clinicopathological definition of Waldenstrom's macroglobulinemia (WM), which were prepared in conjunction with the Second International Workshop held in Athens, Greece during September 2002. WM is an uncommon lymphoproliferative disorder characterized primarily by bone marrow infiltration and IgM monoclonal gammopathy. It should be considered a distinct clinicopathological entity rather than a clinical syndrome secondary to IgM secretion. The underlying pathological diagnosis in WM is lymphoplasmacytic lymphoma as defined by the World Health Organization (WHO) and Revised European-American Lymphoma (REAL) classification criteria. The concentration of monoclonal IgM can vary widely in WM and it is not possible to define a concentration that reliably distinguishes WM from monoclonal gammopathy of undetermined significance (MGUS) and other lymphoproliferative disorders. A diagnosis of WM can therefore be made irrespective of IgM concentration if there is evidence on a bone marrow trephine biopsy of bone marrow infiltration by lymphoplasmacytic lymphoma with predominantly an intertrabecular pattern, supported by appropriate immunophenotypic studies. Simple criteria to distinguish patients with symptomatic WM who require therapy from those with asymptomatic WM and MGUS were also proposed. Patients with clinical features attributable to IgM monoclonal gammopathy but no overt evidence of lymphoma are considered to constitute a distinct clinical group and the term "IgM-related disorders" is proposed. © 2003 Elsevier Inc. All rights reserved.

Objectives. To consider the safety profile and therapeutic value of the combination of estramustine and mitoxantrone in a bimonthly schedule to treat hormone-refractory prostate cancer. The survival of patients with prostate cancer who relapse after androgen ablation is limited and the therapeutic options are restricted. Methods. Twenty-nine patients with relapse after previous treatment were included in the study; however, 3 patients who refused to start treatment were not included in the analysis, leaving 26 eligible patients. The median age was 64 years (range 44 to 82), the World Health Organization performance status ranged from 1 to 3, and the mean prostate-specific antigen level was 103 ng/mL (range 1 to 620). The Gleason score ranged from 2 to 9. The patients received a total of 208 therapeutic cycles (mean 8, range 3 to 24). Every cycle consisted of oral estramustine 140 mg, 3 times a day continuously, and intravenous mitoxantrone 20 mg (total dose). The regimen was repeated every 2 weeks. Results. Twenty-seven percent of patients with measurable soft-tissue disease demonstrated an objective response, which included one complete and six partial responses. Thirteen patients (50%) had a greater than 50% reduction in serum prostate-specific antigen level. The median duration of response was 9.2 months, and the median survival for all patients was 15 months. The most common side effects were neutropenia and thrombocytopenia. Conclusions. The combination of estramustine and mitoxantrone is safe, well tolerated, and relatively active in patients with hormone-refractory prostate cancer. More patients are needed to partake in Phase III studies to establish the survival benefit that this combination may offer. © 2003 Elsevier Inc.

The monoclonal gammopathies are a group of disorders associated with monoclonal proliferation of plasma cells. The characterization of specific entities is an area of difficulty in clinical practice. The International Myeloma Working Group has reviewed the criteria for diagnosis and classification with the aim of producing simple, easily used definitions based on routinely available investigations. In monoclonal gammopathy of undetermined significance (MGUS) or monoclonal gammopathy, unattributed/unassociated (MG[u]), the monoclonal protein is < 30 g/1 and the bone marrow clonal cells < 10% with no evidence of multiple myeloma, other B-cell proliferative disorders or amyloidosis. In asymptomatic (smouldering) myeloma the M-protein is ≥ 30 g/1 and/or bone marrow clonal cells ≥ 10% but no related organ or tissue impairment (ROTI)(end-organ damage), which is typically manifested by increased calcium, renal insufficiency, anaemia, or bone lesions (CRAB) attributed to the plasma cell proliferative process. Symptomatic myeloma requires evidence of ROTL Non-secretory myeloma is characterized by the absence of an M-protein in the serum and urine, bone marrow plasmacytosis and ROTI. Solitary plasmacytoma of bone, extramedullary plasmacytoma and multiple solitary plasmacytomas (± recurrent) are also defined as distinct entities. The use of these criteria will facilitate comparison of therapeutic trial data. Evaluation of currently available prognostic factors may allow better definition of prognosis in multiple myeloma.

Three patients, 2 women and 1 man, with primary (AL) amyloidosis without congestive heart failure are described; all 3 patients presented reduced I-123 metaiodobenzylguanidine(MIBG) myocardial uptake suggesting marked cardiac sympathetic denervation. This is the first time myocardial adrenergic denervation is described in patients with AL amyloidosis without evidence of congestive heart failure; the observed denervation could be implicated in the pathogenesis of cardiac conduction disturbances which are common in this disease.

Background: The efficacy and toxicity of gemcitabine (GEM) and irinotecan (CPT-11) is evaluated in previously untreated patients with inoperable or metastatic pancreatic cancer. Patients and methods: From January 1999 to July 2001, 60 patients with pancreatic cancer (85% stage IV) were enrolled in a two-step extended phase II trial. Patients were treated with gemcitabine (1000 mg/m2 on days 1 and 8) and CPT-11 (300 mg/m2 on day 8) in cycles of 3 weeks. No prophylactic use of recombinant human granulocyte colony-stimulating factor (rhG-CSF) was initially planned. Results: In an intention-to-treat analysis one (1.7%) complete and 14 (23.3%) partial responses were achieved [objective response rate (ORR) 24.7%; 95% confidence interval 14.04% to 35.96%]. Twenty-two (36.7%) and 23 (38.3%) patients had stable and progressive disease, respectively. The median duration of response was 5 months, the median time to tumor progression (TTP) was 7 months and the median overall survival 7 months. One-year survival was 22.5%. Pain improvement and asthenia during treatment were observed in 45% and 43% of patients, respectively; weight gain occurred in 19.5% of patients. Grade 3 anemia occurred in three (5%) patients who required transfusion of six packed red blood cell (RBC) units. Ten (16.7%) additional patients with grade 2 anemia were treated with recombinant erythropoietin. Grade 3 thrombocytopenia occurred in seven (11.7%) patients and grades 3 and 4 neutropenia in 27 (45%). Ten patients developed febrile neutropenia, two of whom died due to sepsis. Prophylactic use of rhG-CSF was eventually required in 93 (28.3%) of 329 administered cycles. Other toxicities were mild. Conclusions: The combination of gemcitabine and irinotecan is an active chemotherapy regimen against pancreatic cancer with a 25% ORR. Toxicity was acceptable for the great majority of patients but with a high percentage of hematopoietic growth factor administration.

To evaluate the activity of thalidomide in Waldenstrom's macroglobulinemia (WM), 20 patients were treated on a dose schedule that escalated from 200 mg/d to 600 mg/d. On an intention-to-treat basis, five (25%) patients achieved a partial response, which was noted within 3 months of treatment. Adverse effects were common and prevented dose escalation of thalidomide in 75% of patients and led to premature discontinuation of treatment in 35%. We subsequently evaluated the oral combination of clarithromycin (500 mg twice per day), low-dose thalidomide (200 mg once daily), and dexamethasone (40 mg once per week). Our preliminary analysis on 12 previously treated patients indicate activity of this regimen in WM: three patients achieved a partial response and two patients demonstrated monoclonal protein reduction of greater than 25%. This combination was associated with a variety of side effects due not only to thalidomide, but also to corticosteroids and to clarithromycin. Our preliminary data indicate that this combination may be a useful salvage regimen for some patients with heavily pretreated macroglobulinemia. © 2003 Elsevier Inc. All rights reserved.

Fludarabine is an active agent for the treatment of Waldenstrom's macroglobulinemia (WM) and its combination with cyclophosphamide has been effective in many patients with low-grade lymphoma and chronic lymphocytic leukemia. Based on these data, we administered the combination of fludarabine (25 mg/m2 IV day 1-3) and cyclophosphamide (250 mg/m2 IV day 1 - 3,) to 11 patients with WM. Most patients had features indicating poor prognosis including median age of 73 years (range 60-84 years), hemoglobin <100g/l in 73%, B2-microglobulin >3mg/l in 64%, symptomatic hyperviscosity in 55% of patients. Only 2 patients were previously untreated, 7 were primary refractory and 2 were relapsing on treatment. The fludarabine-cyclophosphamide combination (FC) was administered every 4 weeks for a total of four courses. Partial response, defined by at least 50% reduction of serum monoclonal protein and of tumor infiltrate at all involved sites was documented in 6 patients (55%) (The median time to response was 4 months). Responding patients demonstrated resolution of disease-related symptoms and correction of anemia. Median time to progression for all patients was 24 months. With a mean follow-up of 28 months, two of six responding patients have progressed so far. The probability of 2-year survival is 70%. This regimen was relatively well tolerated. Complications included neutropenia grade 3 or 4 in 3 patients and thrombocytopenia grade 3 or 4 in 2 patients. There were five infectious episodes including two episodes of neutropenic fever. We conclude that the FC combination appears to be active in patients with WM most of whom were resistant to treatment and had poor prognostic factors. The addition of rituximab to FC requires further investigation.

It is now well established that solid tumors depend on angiogenesis. Promoters and inhibitors of angiogenesis are in balance and antiangiogenic strategies aim at repressing the angiogenic process, thus retarding solid tumor progression. Recent data suggest the importance of angiogenesis in hematologic malignancies and several studies reveal an increased angiogenesis in active multiple myeloma. Angiogenesis seems to be a prominent feature of MM progression, and seems to be correlated with the prognosis and the resistance of MM to chemotherapy. Numerous cell populations and cytokines are involved in angiogenesis in multiple myeloma and antiangiogenic therapy with thalidomide is effective in patients with refractory or relapsed disease. The combination of thalidomide and of other immunomodulatory agents with other therapeutic regimens could lead to more effective management of patients with multiple myeloma.

There is some evidence that taxanes and gemcitabine are effective antitumor agents against small-cell lung cancer (SCLC). A total of 20 chemotherapy-naive patients with extensive disease (ED) SCLC, were treated as a part of the first step of a phase II study, with docetaxel 50 mg/m2 and gemcitabine 1000 mg/m2, both administered on day 1 and 8 every 3 weeks up to a total of six cycles. For patients who progressed after the first cycle or had stable disease after the second cycle of chemotherapy, protocol treatment was stopped and further treatment with the standard cisplatin or carboplatin-etoposide combination was administered. Patients were in the vast majority male smokers with a good performance status. A total of 72 cycles was delivered while patients managed to receive the 78 and 84% of the planned dose of docetaxel and gemcitabine, respectively. Only six patients responded partially and the trial ended prematurely since at least seven responses were required among the first 19 patients. With a median follow-up of 13 months, median time to progression (TTP) was 8 months and median survival 9.6 months. Hematological and non-hematological toxicity was generally acceptable while patients tolerated their treatment reasonably well. In conclusion, docetaxel-gemcitabine showed a modest response rate in chemotherapy-naive patients with ED SCLC. © 2003 Elsevier Science Ireland Ltd. All rights reserved.

Background: This multicenter, prospective phase II study evaluated the safety and efficacy of the combination of docetaxel and vinorelbine in patients with platinum-resistant, paclitaxel-pretreated recurrent ovarian cancer. Patients and methods: Treatment consisted of vinorelbine 25 mg/m2 as a 20-min i.v. infusion (days 1 and 8), and docetaxel 70 mg/m2, as a 1-h i.v. infusion (day 8). Granulocyte colony-stimulating factor support was administered prophylactically on days 12-16. Treatment was repeated every 21 days. Results: Forty-six patients were enrolled. The median number of previous chemotherapeutic regimens was one (range 1-3) with a median treatment-free interval of 4.3 months. Four chemotherapy cycles per patient were administered. Almost 75% of the planned doses for both drugs were given. Forty-one patients are evaluable for response. Three patients (6.5% of all patients; 7.3% of evaluable patients) achieved complete response and eight (17.4% and 19.5%, respectively) a partial response to chemotherapy leading to overall response rates of 23.9% and 26.8%, respectively. Another 34.8% (39.0%) had stable disease. At a median follow-up of 30 months, the median disease-free survival was 13 months, relapse-free survival was 5 months, time to progression was 4.5 months, and overall survival was 9.3 months. Severe toxicities included leukopenia (31%), neutropenia (35%) and febrile neutropenia (20%). Conclusions: The combination of docetaxel/vinorelbine is an effective regimen with manageable toxicity for the treatment of platinum-resistant, paclitaxel-pretreated ovarian cancer.

Objectives. To study retrospectively CA 125, CD44, and epithelial membrane antigen (EMA) expression in renal cell carcinoma and their role as prognostic factors. CD44 is a cell adhesion molecule, and CA 125 and EMA are tumor-associated antigens used in the diagnosis and monitoring of the outcome and response to treatment of various human malignancies. Their expression and prognostic significance after resection of renal cell carcinoma have not been adequately studied. Methods. The expression of CA 125, CD44, and EMA were studied immunohistochemically and correlated with the outcome of 92 patients who underwent nephrectomy for renal cell carcinoma. Results. Positive staining was found for CA 125 in 28 patients (30.43%), CD44 in 48 patients (52.17%), and EMA in 74 patients (80.43%). CA 125 expression was increased in those with higher T stage (P <0.001) and histologic grade (P = 0.007). An inverse relationship was found between EMA expression and grade (P <0.001). The median follow-up was 41.5 months (range 30 to 65). The median survival for positive and negative patients was 34.6 versus 54.3 months for CA 125 (P = 0.0044), 48.3 versus 51.5 months for CD44 (P = 0.4677), and 53.2 versus 34 months for EMA (P = 0.0046). Multivariate analysis showed that CA 125 and EMA expression were independent prognostic factors (P = 0.021 and P = 0.018, respectively). Subgroup analysis showed that CA 125 expression predicted a significantly higher probability of death (28.6% versus 8%, P =0.0413) in patients with T1 or T2 tumors. Conclusions. CA 125 and EMA appear to be useful prognostic markers in renal cell carcinoma. Additional studies are needed to determine the value of these markers as a means of selection for postoperative management. © 2003 Elsevier Inc.

Background: The combination of vincristine and doxorubicin administered as a continuous infusion via an indwelling catheter together with intermittent high-dose dexamethasone (VAD) is an effective primary treatment for patients with symptomatic multiple myeloma. In order to avoid the need for an indwelling catheter, which imposes logistic problems for outpatient administration, several phase II studies have explored the feasibility and efficacy of VAD-like outpatient regimens. We designed a prospective randomized study to compare the objective response rates of two VAD-like outpatient regimens as primary treatment for symptomatic patients with multiple myeloma. Patients and methods: Patients were entered in a randomized study regardless of age, performance status and renal function. One hundred and twenty-seven patients received VAD bolus, which consisted of vincristine 0.4 mg i.v., doxorubicin 9 mg/m2 i.v. and dexamethasone 40 mg p.o. daily for four consecutive days and 132 patients received VAD doxil, which consisted of vincristine 2 mg i.v. and liposomal doxorubicin 40 mg/m2 i.V. on day 1 and dexamethasone 40 mg p.o. daily for 4 days. The two regimens were administered every 28 days for four courses and in courses 1 and 3, in both arms, dexamethasone was also given on days 9-12 and 17-20. Results: An objective response was documented in 61.4% and 61.3% of patients treated with VAD bolus and VAD doxil, respectively. Hematological and non-hematological toxicities were mild or moderate and equally distributed between the two treatment arms with the exception of alopecia, which was more common after VAD bolus, and of palmar-plantar erythrodysesthesia, which was more common after VAD doxil. Conclusions: Our multicenter trial, which included an unselected patient population, indicated that both VAD bolus and VAD doxil can be administered to outpatients and can provide an equal opportunity of rapid response in many patients with multiple myeloma.

Purpose: The objective of this study was to compare the uptake changes of Tc-99m 2-methoxy isobutyl isonitrile (MIBI) and Tc-99m pentavalent dimercaptosuccinic acid (V-DMSA) in multiple myeloma (MM) lesions in response to high-dose chemotherapy (HDC). Materials and Methods: The authors compared Tc-99m MIBI and Tc-99m V-DMSA scans before and after HDC in a patient with focal MM lesions without amyloidosis who had received previous standard chemotherapy as well. Results: HDC had the effect of eliminating all Tc-99m MIBI uptake in the lesions. Tc-99m V-DMSA uptake was increased in lesions presenting significant initial Tc-99m MIBI uptake. In 1 particular lesion that demonstrated this phenomenon, magnetic resonance showed necrosis of the area of MM. Conclusion: The authors consider that the effect of increasing Tc-99m V-DMSA uptake in the absence of an increase in viable plasma cells possibly reflects the treatment-generated inflammatory and fibrotic changes and not necessarily viable tumor tissue. Exclusive focal Tc-99m V-DMSA uptake in this clinical setting could be considered as a sign of effectively treated lesions and not a sign of deterioration.

Rituximab, a chimeric monoclonal antibody, produces response rates of up to 73% in patients with previously untreated indolent non-Hodgkin's lymphoma (NHL), and has high activity when combined with chemotherapy. The purpose of this phase II study was to determine the efficacy and safety of rituximab plus cyclophosphamide, mitoxantrone, vincristine and prednisone (CNOP) chemotherapy in patients with indolent NHL. In all, 42 patients (median age 67 years) with previously untreated follicular, marginal zone or small lymphocytic/lymphoplasmacytic NHL received six infusions of rituximab (375 mg/m2) in combination with six cycles of CNOP. The overall response rate was 90% comprising 30 complete (71%) and eight partial (19%) responses. Although patients with marginal zone lymphoma or International Prognostic Index (IPI) score 3 had lower complete response rates, no significant difference in overall response rate was observed between the histological groups (P = 0.24) or between patients stratified according to IPI score (P>0.05). Median overall survival, time-to-progression and response duration had not been reached after a median 19.5-month follow-up. In all, 31 patients (74%) are currently free from progression and 38 (90%) remain alive. Treatment was well tolerated. One patient (2% experienced grade 3/4 infusion-related toxicity; 13 (31%) grade 3/4 leukopenia and 18 (43%) grade 3/4 neutropenia. Infection was observed in nine patients: eight (19%) grade 1/2 and one (2.4%) grade 3. This study demonstrates that combining rituximab with CNOP achieves high remission rates without significant additional toxicity in patients with previously untreated indolent NHL. Further follow-up will determine response duration and survival.

Background: Waldenstrom's macroglobulinemia (WM) is an unusual lymphoplasmacytoid lymphoma characterized by the presence of a serum monoclonal immunoglobulin M. Although several studies have evaluated possible prognostic factors of this disease, few have focused on the survival and prognosis of symptomatic patients after the initiation of treatment. Patients and methods: Our study included 122 previously untreated patients with a median age of 67 years who required systemic treatment. Multiple variables were analyzed for their prognostic value on survival after initiation of treatment using univariate and Cox regression multivariate analysis. Results: The median overall survival was 106 months. Pretreatment factors associated with shorter survival were age ≥65 years, splenomegaly, B-symptoms (weight loss, fever or night sweats), hemoglobin <10 g/dl, platelets <100 × 106/dl, albumin <3.5 g/dl and bone marrow lymphoplasmacytic infiltrate ≥50%. In the multivariate analysis, the two variables with independent prognostic value were age ≥65 years and hemoglobin <10 g/dl. Furthermore, we were able to divide our patients into three risk groups based on the presence of two, one or none of these two adverse prognostic factors. The median survival times in the high-, intermediate- and low-risk groups were 46 months, 107 months and 172 months, respectively (P <0.0001). Discussion: Our findings suggest that advanced age and anemia appear to be the two dominant prognostic factors for survival after initiation of treatment in patients with WM. These two readily available parameters can stratify the patients into three distinct subgroups and may help the selection of appropriate treatment.

The purpose of this prospective phase II trial was to investigate the safety and efficacy of a modified baseline BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone) regimen in the treatment of intermediate and advanced stage Hodgkin's disease (HD). From October 1997 to November 2001, 51 consecutive, previously untreated patients with stage IIA (bulky), IIB, III, and IV disease were treated with a modified baseline BEACOPP regimen with the etoposide administered i.v. on day 1 and orally at a dose of 100 mg/m2, on days 2 and 3. Each patient was scheduled to receive eight courses of BEACOPP with consolidation radiotherapy to bulky (≤5 cm) or residual disease. There were 25 males and 26 females with a median age of 32 yr (16-65 yr); 80.3% of the patients had nodular sclerosis HD, 41% had bulky disease (≥5 cm), 10 were in stage IIA (bulky ≥10 cm), 15 in stage IIB, 19 in stage III, and seven in stage IV. Thirty-seven patients (72.5%) achieved a complete response and 17.6% partial response. No significant difference in overall response rate was observed between patients with: (i) 0-2 vs. ≥3 negative prognostic factors, (ii) in stage II vs. stages III/IV, LDH level, and bulky disease. With a median follow up period of 39.5 months, actuarial 3-yr survival rate is 82% and time to progression rate 72.5%. Treatment with this combination was well tolerated. Grades 3 and 4 leukopenia and neutropenia occured in 26% and 28% of the patients, respectively, whereas in 16.3% of the patients infection was observed. Support with granulocyte colony-stimulating factor was given to 59% of the patients. No case of secondary MDS/leukemia has been observed. The results of the present study demonstrate that the modified baseline BEACOPP regimen with radiotherapy used in our patients was well tolerated and effective therapy for intermediate and advanced stage HD. Further follow up time is required to evaluate long-term toxicity.

Background: We investigated the efficacy and safety of 2 cycles of adjuvant chemotherapy with carboplatin, etoposide and bleomycin (CEB 90) in patients with high-risk clinical stage I or stage IM non-seminomatous germ cell tumours (NSGCT). Patients and Methods: A total of 52 consecutive patients (22 patients with high-risk histological features [vascular invasion, presence of embryonal carcinoma, absence of yolk sac tumour] and 30 with tumour marker activity post-orchidectomy-stage IM) were entered into this prospective study. Chemotherapy consisted of carboplatin 400mg/m 2 or AUC 5 (day 1), etoposide 165mg/m2 (days 1-3) and bleomycin 30 mg (days 1, 8, 15). Chemotherapy was repeated every 3 weeks. Results: During a median follow-up of 112 months (range, 10 to 174 months), two patients with stage IM relapsed. These cases had a disseminated, marker-positive germ cell tumour (GCT), extensively involving both liver and lungs in the first case and para-aortic lymph nodes and lung in the second one; both patients died of the tumour after a number of salvage chemotherapy (including high-dose therapy) regimens. Fifty patients (96%) are alive and disease-free. Two cycles of CEB90 were well tolerated and the only side-effects were myelotoxicity and alopecia. Conclusion: Despite the general consensus that ciplatin-based chemotherapy is superior to carboplatin-containing regimens in testicular cancer, 2 cycles of CEB 90 may be an equally effective treatment option as adjuvant therapy for high-risk clinical stage I and IM patients.

Angiogenesis represents an essential step in tumor proliferation, expansion, and metastasis. Tumor cells may express both proangiogenic and/or antiangiogenic factors. Under normal circumstances, angiogenesis is controlled through the equilibrium of these factors. This balance is disrupted in malignancy, resulting in promotion of angiogenesis. Among angiogenic molecules, VEGF appears to have a central role in the angiogenic process: it is the target of many proangiogenic factors, but it also regulates molecules that are implicated in endothelial proliferation. It has been suggested that VEGF may be a proximate angiogenic factor through which others act. The degree of angiogenesis and the expression of angiogenic factors have been associated with prognosis in several human neoplasms. In addition, angiogenesis offers a theoretically selective target for anticancer therapy, since it is only required for wound healing, endometrial proliferation, and pregnancy in healthy individuals. Antiangiogenic cancer treatment is still largely experimental and its clinical potential is currently being studied in clinical trials. Thalidomide, a drug with antiangiogenic properties, has shown significant efficacy in patients with relapsed or refractory multiple myeloma. In addition, an anti-VEGF monoclonal antibody prolonged survival in patients with advanced colorectal and renal cell carcinoma. Although these results are encouraging, selection of patients is essential in order to target populations most likely to benefit from antiangiogenic therapy. © 2003 Elsevier B.V. All rights reserved.

Purpose: To investigate the possibility of measuring the gene-specific DNA damage after therapeutic exposure to nitrogen mustards and to examine its relationship with the clinical response. Experimental Design: The kinetics of gene-specific monoadducts and interstrand cross-link formation/repair were measured in the p53 and N-ras genes. DNA extracted from human peripheral lymphocytes following in vitro exposure to melphalan or therapeutic exposure to melphalan or cyclophosphamide was used. Results: When lymphocytes were treated in vitro with biologically relevant doses of melphalan, monoadducts accumulated rapidly in both p53 and N-ras genes, reaching maximal levels within 2 h, whereas the highest interstrand cross-link levels were found within 8 h. Thereafter, the adducts were repaired with half-lives of 14.5 ± 0.3 h (p53) or 18.8 ± 1.5 h (N-ras) for monoadducts and 12.4 ± 0.8 h (p53) or 14.1 ± 2.2 h (N-ras) for interstrand cross-links. Moreover, peak levels of monoadducts in both genes were observed 2 h after treatment in peripheral leukocytes from patients with multiple myeloma treated with high-dose i.v. melphalan, supported by autologous stem cell transplantation, whereas interstrand cross-links were maximal within 8 h. Of seven patients examined, the three who showed the least levels of DNA damage did not respond to the high-dose melphalan. Conclusions: This is the first report showing that it is feasible to measure gene-specific DNA damage in a readily accessible tissue of humans exposed to bifunctional alkylating drugs and to examine, at the level of the individual patient, the relationships between the induction/repair of cytotoxic DNA damage and clinical response or long-term complications.

Recently completed phase II trials and retrospective analyses conducted outside the United States, primarily in Europe and Australia, have confirmed results of landmark US trials that established the efficacy of thalidomide in multiple myeloma. These trials evaluated thalidomide alone or in combination in patients with heavily pretreated relapsed/refractory multiple myeloma. Single-agent thalidomide induced objective responses in approximately one third of patients and prolonged survival by approximately 1 year. These trials also indicated a possible dose-response relationship of thalidomide and identified several poor prognostic factors, including advanced age, high lactose dehydrogenase level, low platelet count, and low hemoglobin level. The combination of thalidomide with dexamethasone increased overall response by approximately 20% and reduced the time to response compared with thalidomide alone. In addition, lower doses of thalidomide used in the combination may increase patient tolerability. Finally, thalidomide in combination with chemotherapy yields response rates of approximately 60%, with median survival times of approximately 18 months. Randomized trials are needed to confirm these results and further explore the role of thalidomide in these treatment settings. © 2003 Elsevier Inc. All rights reserved.

Purpose: In 1999, investigators reported promising results of a phase II study of thalidomide in patients with resistant multiple myeloma (MM). Since then, various trials of thalidomide alone and in combination with other agents have been tested in patients with resistant and, more recently, untreated MM. In addition, preliminary results of phase I studies of the immunomodulatory derivatives (IMiDs) of thalidomide have been recently reported. Design: We reviewed and report the results of clinical trials of thalidomide and the IMiDs, as well as the pharmacology, mechanism of action, and toxicity of these agents. Results: Thalidomide has demonstrated significant activity in both resistant and previously untreated multiple myeloma. Combination therapy with dexamethasone increases response rate, even in patients previously resistant to both drugs given as single agents. More recent studies of thalidomide with dexamethasone in previously untreated patients are highly encouraging. The addition of chemotherapy to thalidomide and dexamethasone may further increase response rates, but its effect on patient survival has not been clarified. Preliminary results of trials of IMiD-3 indicate that this agent is active in resistant myeloma and has a toxicity profile different from that of thalidomide. Conclusion: Many studies have confirmed the activity of thalidomide in MM, as well as an improved response with dexamethasone. Newer thalidomide derivatives with reduced toxicity (neuropathy, teratogenicity) are also promising. Thalidomide with dexamethasone may now represent the treatment of choice for previously untreated patients. Further studies with these and other novel agents early in the course of myeloma may improve complete remission rates and frequency of long-term control. © 2003 by American Society of Clinical Oncology.

CD40 ligand (CD40L, CD154) is overexpressed on T and B cells in systemic lupus erythematosus (SLE). Monocytes have been shown to contribute to immune-mediated pathology in SLE and to express CD40L under certain conditions. Therefore, we studied CD40L expression on lupus monocytes ex vivo, as well as after activation in vitro. A highly significant sevenfold increase in the frequency of CD40L-expressing peripheral monocytes from 23 SLE patients, compared to 16 healthy individuals (mean percentage of CD40L+CD14+ among CD14+ cells, 11.7 versus 1.6), was found by flow cytometry. Increased CD40L expression on monocytes correlated significantly with disease activity, elevated γ-globulin serum levels, as well as increased CD40L expression on T cells. CD40L expression by lupus monocytes was verified at both the mRNA and protein levels, while LPS stimulation was found to upregulate CD40L mRNA accumulation and surface protein expression. CD40L expression on activated lupus monocytes within anti-CD3-stimulated, mononuclear cell cultures was also enhanced compared to control-derived monocytes. These novel findings underscore the multiplicity of pathways through which monocytes may contribute to SLE pathology and suggest that T cell-independent CD40L-mediated cell to cell interactions may be also involved in humoral immune activation in SLE. © 2002 Elsevier Science (USA).

We conducted a phase III study in patients with advanced colorectal carcinoma (ACC). The total number of patients randomized from October 1993 until July 1998 was 192, whereas therapy was started on 179 and 158 (82.3%) have been evaluable. The treatment schedules consisted of weekly bolus administration for 6 weeks of 5-fluorouracil (5-FU), 600 mg/m2 (arm I) versus 5-FU (500 mg/m2) intravenous bolus and interferon-α, 5 MU subcutaneously, three times a week (arm II) versus leucovorin 200 mg/m2 in 2-hour infusion and 5-FU 500 mg/m2 intravenous bolus at the midtime of leucovorin infusion (arm III) followed by a 2-week rest period. Treatment was continued for six cycles or until progression. This study failed to show any superiority of the modulated 5-FU versus single administration of 5-FU. There were no significant differences between the three arms in the overall response rate (10.3% versus 11.3% versus 12.9%, p = 0.95), the time to tumor progression (median, 3.9 versus 3.8 versus 6.0 months, p = 0.59), or survival duration (median, 14.7 versus 12.4 versus 16.3 months, p = 0.71). The incidence of severe (grades III and IV) toxicity was significantly higher in patients in arm II and III (24.5% and 18.6%) versus arm I (6.0%) (p = 0.01). Because modulated 5-FU failed to show superiority versus 5-FU, new agents and new strategies are needed for the treatment of advanced colorectal carcinoma.

The treatment of patients with recurrent low-grade lymphoma with the combination of fludarabine, mitoxantrone and dexamethasone has been associated with significant activity but has also caused frequent infectious complications. We designed a phase II study for previously untreated patients with the combination of fludarabine and mitoxantrone but without steroids. Our aim was to assess the activity of this combination as primary treatment for low-grade lymphoma and to avoid the additional immunosuppression induced by dexamethasone. Twenty seven patients with low-grade lymphoma received fludarabine 25 mg/m2/day IV on days 1-3 and mitoxantrone 10 mg/m2 IV on day 1. The treatment was repeated every 28 days for a maximum of six cycles. Twenty patients (74%) achieved an objective response including 12(44%) complete and 8(30%) partial responses. The main toxicity was grade III or IV neutropenia, which occurred in 40% of patients but there were no severe opportunistic infections. The median time to progression for all patients was 32 months. With a median follow-up of 33.4 months, six patients have died and the probability of survival at 3 years is 75%. We conclude that the fludarabine and mitoxantrone regimen is safe and effective for newly diagnosed patients with low-grade lymphoma who require treatment. Prospective randomized trials are needed in order to assess the impact of this treatment on patients' survival.

BACKGROUND. Adverse effects of paclitaxel and carboplatin have been well described; however, pulmonary toxicity after patients receive this regimen has not been investigated extensively. METHODS. To clarify this issue, 33 consecutive patients who were treated with paclitaxel and carboplatin underwent prospective evaluation of respiratory function, which included pulmonary symptoms, pulmonary function tests (PFTs), arterial blood gas levels, and radiographic studies. Assessment was performed before and after completion of chemotherapy in all patients. Patients with substantial declines in PFTs, defined as a decline ≥ 20 percent in forced expiratory volume in 1 second (FEV1), total lung capacity (TLC), or diffusion capacity for carbon monoxide (DLCO), were reassessed 5 months later. RESULTS. After chemotherapy, there were no significant changes in forced vital capacity (FVC; 111% ± 21% of the predicted value before chemotherapy vs. 111 ± 20% of the predicted value after chemotherapy), FEV1 (108% ± 24% of the predicted value before chemotherapy vs. 107% ± 22% of the predicted value after chemotherapy), FEV1/FVC ratio (79% ± 8% before chemotherapy vs. 78% ± 6% after chemotherapy), alveolar volume (VA; 95% ± 14% of the predicted value before chemotherapy vs. 96% ± 14% of the predicted value after chemotherapy), or TLC (96% ± 14% of the predicted value before chemotherapy vs. 97% ± 13% of the predicted value after chemotherapy). In contrast, there was a significant decline in DLCO (101% ± 20% of the predicted value before chemotherapy vs. 96 ± 21% of the predicted value after chemotherapy; P < 0.05). Arterial blood gas levels did not change after treatment. No patient had decreased FEV1 or TLC levels by ≥ 20%, whereas 4 of 33 patients (12%) exhibited a substantial decline (≥ 20%) in DLCO that persisted 5 months after treatment (DLCO at baseline, immediately after chemotherapy, and 5 months after the completion of chemotherapy, respectively: 99% ± 36% of the predicted value vs. 75% ± 28% of the predicted value vs. 74% ± 31% of the predicted value; P < 0.05). None of the 33 patients developed respiratory symptoms or had radiologic signs suggestive of lung toxicity. Among the various risk factors examined, baseline DLCO and FEV1 levels were associated with changes in DLCO post-treatment. CONCLUSIONS. This prospective analysis showed that the combination of paclitaxel with carboplatin induced an isolated decrease in DLCO level in the absence of clinical or radiologic evidence of toxicity. Further studies are needed to clarify whether this reduction in DLCO is predictive of subsequent pulmonary impairment. © 2002 American Cancer Society.

Solitary bone and extramedullary plasmacytomas are rare plasma cell proliferative disorders. Their diagnosis is based on histologic confirmation of monoclonal plasma cell infiltration of a single disease site and on the exclusion of systemic myeloma. For both entities, the treatment of choice is localized radiotherapy. With modern radiotherapy and with a total dose of at least 4000 cGy, the risk for local recurrence is less than 5%. There is no role for systemic chemotherapy in the management of these disorders. Approximately 30% of patients with solitary bone plasmacytoma (SBP) remain disease-free for several years; some of these patients may be cured. Patients with the best prognosis are those in whom the monoclonal protein disappears by 1 year after radiotherapy. The prognosis of patients with solitary extramedullary plasmacytoma (SEP) appears to be better than for patients with SBP because approximately 70% of patients with SEP remain disease-free at 10 years. With more sensitive staging procedures, the diagnosis of SBP and SEP may become less common, but the number of patients with prolonged stability and cure may increase.

Introduction: During the last few years epirubicin (E) and mitoxantrone (M) (Novantrone) have been used in the treatment of non-Hodgkin's lymphoma (NHL), because of their favorable principal profile. In particular, M has less severe non-hematological toxicity. Patients and methods: A randomized multicenter phase III study was conducted in order to compare the efficacy and toxicity of CEOP and CNOP in intermediate- and high-grade NHL. CEOP (arm A) consisted of cyclophosphamide 1000 mg m-2, vincristine 2 mg, E 70 mg m-2 on day 1 and prednisone 60 mg on days 1-7. The CNOP regimen (arm B) was identical to CEOP except for replacement of E by M at a dose of 12 mg m-2. Randomization was stratified according to stages I-IV. From September 1993 to March 1999, 249 patients registered for the trial. Patient characteristics were equally distributed in the two arms, except for age and International Prognostic Index (IPI) groups. Results: There were no significant differences between the two groups in the rates of complete (CR) and partial response (PR). The overall response rate was 78% in arm A (57% CR, 21% PR) and 82% in arm B (60% CR, 22% PR). With a median follow-up time of 47.3 months, the median survival was not reached in arm A, while it was 39.5 months in arm B (P=0.09). Three-year survival rates were 62.5% for CEOP and 51.5% for CNOP. There was no significant difference regarding the time to progression between the two groups (29.7 vs. 18.5 months); furthermore the median duration of CRs was 71.6 and 49 months for CEOP and CNOP, respectively (P=0.07). The therapeutic efficacies of both regimens were equivalent among the four IPI groups. More alopecia was observed in arm A. WHO grade >2 neutropenia was more frequent in arm B. Supportive treatment with G-CSF was given to 22 and 24 patients, respectively. Conclusion: There were no significant differences in terms of overall response rates, overall survival and time to progression between CEOP and CNOP in the treatment of intermediate- and high-grade NHL. Patients with low or low intermediate IPI risk treated with either CEOP or CNOP showed significantly better survival, response rates and time to progression than those with high intermediate or high IPI risk. Therefore, new improved therapeutic approaches should be developed for the treatment of high IPI risk patients.

Purpose: Waldenström's macroglobulinemia (WM) is a low-grade lymphoplasmacytic lymphoma in which CD20 is usually expressed on tumor cells. There is evidence that patients with WM may benefit from treatment with the anti-CD20 monoclonal antibody rituximab. We performed a prospective phase II study to clearly define the activity of rituximab in patients with this disease. Patients and Methods: Twenty-seven patients with WM were treated with rituximab 375 mg/m2 intravenously (IV) for 4 weeks. Three months after completion of rituximab, patients without evidence of progressive disease received repeat 4-week courses of this agent. All patients were symptomatic, their median age was 72 years, and 15 patients were previously untreated. Results: Twelve patients (44%; 95% confidence interval, 25.5% to 64.7%) achieved a partial response after treatment with rituximab. Median time to response was 3.3 months (range, 2.2 to 7.1 months). Responses occurred in six (40%) of 15 previously untreated patients and in six (50%) of 12 pretreated patients. Patients with a serum immunoglobulin M less than 40 g/L had a significantly higher response rate. The median time to progression for all patients was 16 months, and with a median follow-up of 15.7 months, nine of 12 responding patients remain free of progression. Treatment with rituximab was well tolerated, with approximately one fourth of patients experiencing some mild form of infusion-related toxicity, usually fever and chills. Conclusion: Our prospective data indicate that rituximab is well tolerated and active in patients with WM. Previously untreated and pretreated patients seem to benefit equally. Repeat 4-week courses of rituximab may prolong the duration of response of the disease, but this observation requires confirmation in prospective, randomized trials. Furthermore, studies that will combine rituximab with chemotherapy may be relevant. © 2002 by American Society of Clinical Oncology.

Determinations of the cadmium content of a wide variety of foodstuffs from the Greek market were carried out. The values detected ranged from <0.1 ng g-1 in alcoholic beverages to 1595.8 ng g-1 in large snails. The highest values were observed in molluscs and crustaceans (117.4ng g-1), followed by leafy vegetables (28.3 ng g-1), potatoes (22.3 ng g-1) and organs and offal (20.7 ng g-1), whereas the other food categories had a lower cadmium content. The results are comparable with those from the rest of Europe. Preliminary analytical data on the cadmium content of food samples of organic cultivation showed significantly lower values compared with those of samples of conventional produce.

Objectives. Ifosfamide, paclitaxel, and cisplatin have moderate single-agent activity in patients with metastatic or recurrent cancer of the uterine cervix. We administered a combination of these three agents to a large number of patients with metastatic or recurrent cervical cancer to evaluate its activity. Methods. Sixty patients were treated on an outpatient basis with Ifosfamide (I) 1500 mg/m2 intravenously over 1 h on Days 1-3, paclitaxel (T) 175 mg/m2 as a 3-h intravenous infusion on Day 1, and cisplatin (P) 75 mg/m2 intravenously over 2 h on Day 2 with granulocyte colony-stimulating factor (G-CSF) support. The chemotherapy was repeated every 4 weeks for a maximum of six courses. Results. Fifty-seven patients received at least two courses of treatment and are evaluable for response. Twenty-six patients (46%) achieved an objective response, including 19% complete and 27% partial responses. The median duration of response was 11.5 months and the median time to progression and survival for all patients were 8.3 and 18.6 months, respectively. Patients with excellent performance status, with disease recurrence outside the radiation field, and with nonsquamous tumors had the highest response rate and best survival. Some degree of neurotoxicity occurred in 44% of patients. Grade 3 or 4 toxicity included granulocytopenia in 26% of patients, anemia in 13%, thrombocytopenia in 7%, and neurotoxicity in 3%. Conclusion. The ITP regimen is relatively well tolerated and moderately active in patients with metastatic carcinoma of the uterine cervix. Patients more likely to benefit are those with nonsquamous histology, with excellent performance status, and with disease recurrence outside the radiation field. © 2002 Elsevier Science (USA).

Waldenström's macroglobulinemia is a low-grade lymphoplasmacytoid lymphoma characterized by CD20 expression on malignant cells. Several studies have indicated that the anti-CD20 monoclonal antibody rituximab has activity against this disease. Thus, we performed a prospective study in which 17 previously untreated patients with symptomatic macroglobulinemia were treated with rituximab 375 mg/m2 intravenously for 4 weeks. Three months after completion of rituximab, patients without evidence of progressive disease received repeat 4-week courses of this agent. Six patients (35%) achieved a partial response after extended treatment with rituximab. Median time to response was 3 months. The median time to progression (TTP) for all patients was 13 months. One of 6 responding patients has progressed at 10 months, while the other 5 patients remain progression free with a follow-up range of > 22-40 months. Eight patients (47%) were rated as stable disease, and their median TTP was 9 months. Treatment with rituximab was well tolerated and was not associated with myelosuppression; one third of the patients experienced infusion-related toxicity, usually fever and chills of mild degree. Our prospective trial of extended rituximab therapy for previously untreated patients with Waldenström's macroglobulinemia indicates that this agent is active, well tolerated, and might be associated with a long period without the need for further treatment. Studies that will combine rituximab with chemotherapy or with other monoclonal antibodies might be of interest.

Monoclonal gammopathy of undetermined significance (MGUS) is a relatively common condition among individuals older than 70 years. The actuarial risk of MGUS progression to an overt plasma cell malignancy (PCM) after 20 years of follow-up has been reported to be as high as 30%. The purpose of this study was to evaluate the incidence and evolution of MGUS in a Greek population: 1564 consecutive patients older than 50 years who were admitted to the Department of Clinical Therapeutics at the University of Athens School of Medicine for various reasons over a 26-month period were evaluated with serum protein electrophoresis. In cases in which a monoclonal protein was detected, a panel of tests was performed to rule out an underlying plasma cell malignancy (PCM). Serum levels of interleukin (IL)-6, IL-6-soluble receptor (IL-6SR), IL-1 beta, and transforming growth factor beta 1 were also measured in the MGUS cases. Patients with MGUS were monitored at regular intervals for evidence of multiple myeloma or other PCMs. The incidence of MGUS was 4% and there was a positive correlation with increasing age. The median value of serum M peak was only 5.3 g/l. After a median follow-up of 71 months, only two patients developed multiple myeloma (60 and 75 months after initial diagnosis). Our data are consistent with those of other epidemiological studies regarding the incidence of MGUS, but the monoclonal protein levels and the probability of evolution to a malignant plasma cell disorder appeared to be lower in our study than in other series. Our data support the hypothesis that individuals with low M peak values require only regular annual follow-up examinations.

Purpose: We conducted this randomized study comparing the activity and toxicity of paclitaxel and gemcitabine (PG) and paclitaxel and carboplatin (PC) combinations for the treatment of advanced non-small-cell lung cancer (NSCLC). Patients and Methods: Chemotherapy-naive patients were randomized to paclitaxel 200 mg/m2 on day 1 plus either carboplatin at an area under the concentration-time curve of 6 on day 1 (group A) or gemcitabine 1,000 mg/m2 on days 1 and 8 (group B) every 3 weeks. A retrospective cost analysis was conducted using Student's t test to compare independent samples between groups. Results: A total of 509 patients (group A, 252 patients; group B, 257 patients) were enrolled; all characteristics were well balanced. The median survival time was 10.4 months (95% confidence interval [CI], 8.8 to 12 months) for group A and 9.8 months (95% CI, 8.0 to 11.7 months) for group B (P = .32). Respective 1-year survival rates were 41.7% and 41.4%. The response rate for group A was 28.0% (2% complete response [CR], 26% partial response [PR] [95% CI, 22% to 34%]), and the response rate for group B was 35.0% (5% CR, 30% PR) [95% CI, 29% to 41%]) (P = .12). Toxicity was mild. Grades 3/4 neutropenia, thrombocytopenia, and anemia for groups A and B were seen in 15% and 15%, 2% and 1%, and 5% and 2%, respectively. The mean total cost (outpatient clinic visits plus chemotherapy drug fee) for group A (€ 7,612.64) versus group B (€ 7,484.77) was not statistically significant (P < .66). Conclusion: The PG combination is as equally active and well tolerated as the PC combination in patients with advanced NSCLC. © 2002 by American Society of Clinical Oncology.

Background: The usefulness of tumor volumetry in ovarian epithelial cancer has never been intensively investigated. The aim of the present study was to determine the value of quantitative analysis of tumor volume as a predictive method for response to treatment and as a prognostic method for disease outcome. Materials and Methods: Seventy-five women with advanced ovarian cancer who presented with measurable disease on CT scan prior to chemotherapy were retrospectively studied. The patients were treated with platinum-based chemotherapy. The median follow-up was 113.36 weeks. An independent radiologist identified and delineated tumor contours in each slice of sequential CT scans before and after therapy. Volumetry was measured with a three-dimensional approach by utilizing a digitizer and a specific algorithm on a software computed program. Results: Data were analyzed according to initial and to residual tumor volumes. Patients with low initial volume of <52 cm3 exhibited higher responses (p<0.01), while patients with medium (52-165 cm3) or high (> 165 CM3) initial tumor volume had a shorter time to progression (p<0.01). Patients without or with low residual volume of <35 cm3 were found to have a longer time to progression (p<0.05) and longer survival (p<0.01 and p<0.05). In addition, serum CA 125 levels followed precisely tumor volumetry for both initial and residual disease. Conclusion: Tumor volumetry in advanced ovarian cancer was found to have predictive value for response to platinum-based chemotherapy. Initial tumor volume has prognostic significance only for the time to progression, whereas residual tumor volume has for both time to progression and survival.

Background: The aim of this study is firstly to determine the response rates and toxicity of two regimens containing vinblastine (VBL) in combination with interferon-gamma (IFN-γ) in the treatment of patients with advanced renal cell carcinoma (RCC), and secondly to evaluate the additional efficacy of 13-cis retinoic acid (13-CRA) in RCC. Methods: Twenty-nine patients were included in the first trial (Trial 1) and 40 in the second one (Trial 2). The therapy given in Trial 1 consisted of VBL 0.15 mg/kg i.v. every 2 weeks and IFN-γ 100 μg s.c. 3 times weekly. In Trial 2, the therapy consisted of the same two drugs, in the same doses, plus oral 13-CRA 40 mg/day. Results: In Trial 1 there were 3 (10.3%) patients with complete response, 3 (10.3%) patients with partial response, 8 (27.6%) patients with stable disease and 15 (51.7%) patients with progressive disease. In Trial 2, there was no complete response, however, 3 (7.5%) patients had partial response. Additionally, 15 (37.5%) patients maintained stable disease and 14 (35%) patients had progressive disease. In Trial 1, the median survival was 12.56 months (95% CI, 6.8-18.3, range 0.59-42.49) and the median time to progression was 3.21 months (95% CI, 1.7-4.7, range 0.03-42.49). In Trial 2, the median survival was 9.54 months (95% CI, 5.9-13.1, range 0.43-24.1) and the median time to progression was 3.9 months (95% CI, 0.8-7, range 0.26-24.1). In Trial 1, granulocytopenia grade 3 and 4 appeared in 5 (17.2%) patients and anaemia grade 3 in 1 (3.4%) patient. In Trial 2, there were grade 3 toxicities, as granulocytopenia in 5 (12.5%) patients, anemia in 4 (10.0%) patients, stomatitis in 3 (7.5%) patients, fatigue/ malaise in 3 (7.5%) patients and 1 (2.5%) had diarrhea. No toxic deaths occurred in both studies. Conclusion: The use of IFN-γ does not enhance the low response of VBL-based chemotherapy. The additional administration of 13-CRA with the combination of VBL and IFN-γ does not add to the efficacy of this combination in patients with advanced renal cell carcinoma. New active agents are needed to treat patients with this disease. Copyright © 2002 S. Karger AG, Basel.

Background: To better understand the molecular background of B-cell overactivity characterizing systemic lupus erythematosus (SLE), we examined the expression of the CD22 co-receptor and of kinase Lyn, which are involved in signaling inhibitory pathways, in B cells from patients with SLE. Methods: Two-color flow cytometry was used to study the expression of surface antigens on freshly isolated peripheral B cells from patients with SLE, disease-control patients, and healthy volunteers. Intracellular kinases Lyn and Syk were analyzed using Western immunoblots, and differences at the messenger RNA (mRNA) level were evaluated using semi-quantitative polymerase chain reaction (PCR). Results: Expression of B-cell surface CD22 was intact in patients with SLE, but expression of the B-cell kinase Lyn was significantly decreased in resting, as well as in anti-sIgM-stimulated B-cell-enriched cell lysates obtained from 66% of patients with SLE. Lyn deficiency was disease-specific and unrelated to disease activity. Expression of B-cell kinase Syk was similar in all study groups. Semiquantitative PCR revealed that Lyn mRNA was significantly decreased in lupus patients with decreased Lyn protein expression, suggesting that Lyn deficiency may be caused at least in part by defects at the transcription level. Conclusions: Decreased expression of Lyn in some patients with SLE represents a B-cell defect that may enhance our understanding of SLE molecular pathogenesis by providing rational therapeutic targets.

Objectives: The purpose of the study was to evaluate, in a selected group of myeloma patients with favorable prognosis, the effect, on response and survival, of polychymotherapy compared with melphalan-prednisone, plus interferon in both arms. Methods: Eighty-nine previously untreated patients with multiple myeloma and prognostic factors indicating a good prognosis were randomized to either oral melphalan plus prednisone (MP) in combination with recombinant interferon-α (rIFN-α) or combination chemotherapy with vincristine, carmustine, melphalan, cyclophosphamide, and prednisone (VBMCP) alternating with rIFN-α. The two treatment groups were comparable in terms of pretreatment characteristics. Results: The overall response rate was 67.4% (2.3% complete remission, 65.1% partial response) in the MP/IFN-α group and 69.1% (14.3% complete remission, 54.8% partial response) in the VBMCP/IFN-α group (p = 0.59). There were no differences also in response duration and overall survival between the two treatment groups. The median response duration was 39.1 months in the MP/IFN-α group and was not reached in the VBMCP/IFN-α group (p = 0.6). Overall survival was long in both treatment groups. The estimated 5-yr survival was 66% and 62% in the MP/IFN-α and VBMCP/IFN-α group, respectively (p = 0.8). Toxicity was modest and treatments were well tolerated. Neutropenia (WHO grade 3 or 4) was higher, but not statistically significant, in the VBMCP/IFN-α group. Conclusions: The results of the study show that in myeloma patients with good prognosis, combination chemotherapy alternating with interferon-α has no advantage over conventional MP plus interferon-α, in regard to response rate, response duration, and overall survival of patients. © Munksgaard 2001.

BACKGROUND. Cancer antigen 15-3 (CA 15-3), a circulating marker that determines secreted products of the polymorphic MUC1 gene, has been established as a convenient tool for monitoring breast carcinoma patients. METHODS. The authors investigated alterations of soluble CA 15-3 in 57 postoperative breast carcinoma patients while they were receiving intensified adjuvant chemotherapy with granulocyte colony stimulating factor (G-CSF) support: 26 patients had American Joint Committee on Cancer (AJCC) Stage 11, and 31 patients had AJCC Stage III breast carcinoma. Serial CA 15-3 values recorded thoughout the treatment were compared with baseline values, analyzed for correlation with hematologic and biochemical parameters, and compared with clinicopathologic characteristics and patient outcome. At a median follow-up time of 32 months, 47 of these patients remained relapse-free. RESULTS. A twofold increase of CA 15-3 was detected at the end of the second week of treatment, remained significantly elevated in most patients at above the cutoff level of 30 U/mL throughout the treatment period (P < 0.0001), and subsided to pretreatment values 1-2 months after treatment cessation. CA 15-3 values were found to be associated strongly with absolute neutrophil count, serum lactate dehydrogenase, and alkaline phosphatase. The median values and the kinetics of tumor markers did not differ over time in regard to hormonal receptor status and disease recurrence. CONCLUSIONS. These data provide strong evidence that G-CSF administration can induce elevation of CA 15-3 and indicate that false-positive results should be considered when evaluating CA 15-3 in patients who are receiving G-CSF. It is speculated that this phenomenon occurs through the induction of MUC1 antigen of unknown origin by G-CSF. Experimental investigation of this clinical observation is warranted. © 2001 American Cancer Society.

Data of randomized studies of adjuvant and neoadjuvant chemotherapy for patients with muscle-invasive bladder cancer were reviewed. Four adjuvant studies have been published. The interpretation of their data is compromised primarily because of small patient numbers. Thus, a possible survival advantage cannot be documented, and significantly larger, prospective studies are needed. However, there is some evidence of improved disease-free survival for patients with non-organ-confined tumors treated with cisplatin-based combination chemotherapy. More data are available for neoadjuvant chemotherapy. The already published randomized studies, including a large trial of who was designed to detect a 10% survival benefit, do not indicate a significant advantage for neoadjuvant chemotherapy. Radical cystectomy remains the standard treatment to which other therapeutic modalities must be compared. Copyright © 2001 by W.B. Saunders Company.

During the last years, a number of assays have been developed aiming at predicting the most effective chemotherapy regimen for each individual, avoiding possible toxicity of ineffective drugs. In the present study we have used an in vitro chemosensitivity/chemoresistance assay in order to evaluate cytotoxic treatment in ovarian and breast cancer patients. The assay was applied in 77 ovarian and breast cancer samples and the observed in vitro responses to various chemotherapeutic drugs or combinations of drugs were then correlated to the in vivo responses and the overall clinical data of the examined patients. Direct comparison was possible for 25 cases. The overall positive predictive value of the assay was 50% and the negative predictive value was 57%. However, it was observed that the positive predictive value for ovarian patients was 69% and that the negative predictive value for breast patients was 100%. Therefore this study indicates that although in vitro chemosensitivity/chemoresistance is a valuable assay, further analysis and implications of other factors are required for a general evaluation of cytotoxic treatment for patients with ovarian and breast cancer.

Dose-dense sequential chemotherapy appears to be a promising approach in the management of patients with operable breast cancer. We evaluated the tolerability of such a novel chemotherapeutic regimen in high-risk patients. From February 1995 until September 1997, 49 women with histologically confirmed breast cancer and ≥10 involved axillary nodes were treated postoperatively with three cycles of epirubicin (110 mg/m2) followed by three cycles of paclitaxel (250 mg/m2 in a 3-hour infusion) followed by three cycles of 'intensified' CMF (cyclophosphamide 840 mg/m2, methotrexate 57 mg/m2, fluorouracil 840 mg/m2; E-T-CMF). All cycles were repeated every 2 weeks with G-CSF support. Ovarian ablation with monthly injections of triptorelin for 1 year was performed in premenopausal patients and tamoxifen was prescribed for 5 years to all women with positive receptor status after the completion of chemotherapy. A total of 456 cycles of chemotherapy were administered, 363 (80%) of them at full dose. Forty-seven (96%) patients received all 9 cycles of chemotherapy. Relative dose intensity of epirubicin was 0.98, of paclitaxel 0.97, of cyclophosphamide 0.99, of methotrexate 0.98 and of fluorouracil 0.99. Grade 3-4 toxicities included anemia (8%), leukopenia (8%), peripheral neuropathy (6%), neutropenia (4%), thrombocytopenia (4%), stomatitis (2%), diarrhea (2%), fatigue (2%) and hypersensitivity reaction (2%). Febrile neutropenia occurred in 2 patients. Alopecia was universal. After a median follow-up of 3 years, 11 women (22%) relapsed and 4 (8%) died. The 3-year actuarial disease-free survival rate was 72% and the 3-year overall survival rate 90%. The E-T-CMF regimen is well tolerated, as adjuvant treatment, in patients with operable breast cancer with promising activity and deserves further evaluation in phase III studies. Copyright © 2001 S. Karger AG, Basel.

The purpose of this study was to evaluate the activity and toxicity profile of dose-dense sequential chemotherapy with epirubicin (EPI) and paclitaxel in advanced breast cancer (ABC). From January to September 1997, 41 patients with recurrent or metastatic (stage IV) breast cancer were enrolled in the study. Their median age was 57 (range, 33-77) years and median performance status 0 (range, 0-2). Twenty patients had received adjuvant chemotherapy. The chemotherapeutic regimen consisted of 4 cycles of EPI 110 mg/m2 every 2 weeks followed by 4 cycles of paclitaxel, 225 mg/m2 over 3 hours every 2 weeks. G-CSF was administered prophylactically on days 2-10 of each cycle. 34 (83.0%)patients completed all 8 cycles of chemotherapy. A total of 304 cycles were administered, 259 (85.0%) of them at full dose. Thirty (10.0%) cycles were delivered with a delay. The relative median dose intensities of EPI and paclitaxel were 0.95. Most common grade 3-4 side effects were anemia (15.0%) neutropenia (12.0%), thrombocytopenia (5.0%), nausea/vomiting (10.0%), febrile neutropenia (7.5%), and alopecia (90.0%). Overall, 8 (19.5%) patients achieved a complete and 15 (36.5%) a partial response. Median duration of response was 8.4 (range, 3.1-15.5+) months. After a median follow-up of 18.5 months, median time to progression was 8.7 (range, 0.5-21+) months; median survival has not been reached yet. Dose-dense sequential chemotherapy with EPI and paclitaxel shows promising activity as first-line treatment in ABC. Randomized studies comparing this type of chemotherapy with the classical administration of the two drugs together every 3 weeks are ongoing.

Purpose: To compare the efficacy of two different schedules of epirubicin and paclitaxel, as first-line chemotherapy, in patients with advanced breast cancer (ABC). Patients and Methods: From October 1997 until May 1999, 183 eligible patients with ABC entered the study. Chemotherapy in group A (93 patients) consisted of four cycles of epirubicin at a dose of 110 mg/m2 followed by four cycles of paclitaxel at a dose of 225 mg/m2 in a 3-hour infusion. All cycles were repeated every 2 weeks with granulocyte colony-stimulating factor support. The therapeutic regimen in group B (90 patients) consisted of epirubicin (80 mg/m2) immediately followed by paclitaxel (175 mg/m2 in a 3-hour infusion) every 3 weeks for six cycles. Results: In total, 79 patients (85%) in group A and 72 patients (80%) in group B completed treatment. The median relative dose-intensity of epirubicin was 0.96 in both groups, and that of paclitaxel was 0.96 and 0.97 in groups A and B, respectively. The complete response rate was higher in group A (21.5% v 9% P = .02). Nevertheless, there was no significant difference in the overall response rate between the two groups (55% v 42%, P = .10). Severe neutropenia was more frequently observed with concurrent treatment. After a median follow-up of 16.5 months, median time to progression was 10 months in group A and 8.5 months in group B (P = .27), and median survival was 21.5 and 20 months, respectively (P = .17). Conclusion: The present study failed to demonstrate a significant difference in overall response rate between dose-dense sequential administration of epirubicin and paclitaxel compared with the combination of the two drugs given on the same day, even though the sequential treatment resulted in a significantly higher complete response rate. © 2001 by American Society of Clinical Oncology.

Preliminary evidence suggests that high-dose chemotherapy followed by autologous or allogeneic stem cell transplantation may be effective in some patients with resistant Waldenstrom's macroglobulinemia. During the last 10 years, seven patients with Waldenstrom's macroglobulinemia have received transplants at the MD Anderson Cancer Center, four with autologous and three with allogeneic stem cells. Four patients achieved partial remission, and three patients have remained alive for at least 2 years. Our data confirm the feasibility of high-dose therapy in patients with macroglobulinemia and support the need for prospective studies of this modality in patients with chemosensitive disease.

BACKGROUND. The combination of paclitaxel with a platinum analogue is the preferred chemotherapy regimen in the treatment of advanced epithelial ovarian carcinoma. The alkylating agent ifosfamide has shown activity in refractory or recurrent ovarian cancer. We conducted a Phase II study with the combination of ifosfamide, paclitaxel, and cisplatin for the treatment of newly diagnosed patients with advanced, suboptimally debulked ovarian carcinoma. METHODS. Thirty-five consecutive patients with advanced ovarian carcinoma (International Federation of Gynecology and Obstetrics [FIGO] Stage III or IV) and residual disease larger than 2 cm after staging laparotomy and cytoreductive surgery were treated with paclitaxel, 175 mg/m2, as a 3-hour intravenous infusion on Day 1, cisplatin 75 mg/m2 intravenously over 2 hours on Day 2, and ifosfamide 1500 mg/m2 intravenously over 1 hour on Days 1-3 (with sodium 2-mercaptoethane sulfonate [MESNA] uroprotection). Courses were administered every 3 weeks on an outpatient basis. Granulocyte-colony stimulating factor was given at a dose of 5 μg/kg/day on Days 7-11. RESULTS. Among 26 patients with measurable disease, 22 (85%) achieved an objective response including 15 complete and 7 partial responses. With a minimum follow-up of 46 months, the median overall survival was 52.8 months (range, 5.3-56.6+ mos), whereas the median time to progression for all patients was 22.2 months. The median remission duration for women with measurable disease who responded to treatment was 12.6 months. The treatment was tolerated relatively well without toxic deaths; the most common toxicity was Grade 3 or 4 neutropenia that occurred in 42% of patients. Significant peripheral neuropathy (Grade 2 or higher) developed in 35% of patients. CONCLUSION. The combination of ifosfamide, paclitaxel, and cisplatin is a well-tolerated outpatient regimen with significant activity in the treatment of newly diagnosed FIGO Stage III or IV epithelial ovarian carcinoma. Further evaluation is justified to clearly define the role of ifosfamide as an additional agent to the current platinum and paclitaxel regimens. © 2001 American Cancer Society.

Clinical outcomes were assessed in 68 consecutive patients with multiple myeloma of high or intermediate tumor mass that had responded to VAD or dexamethasone-based therapy and were consolidated with early intensive therapy and autologous stem cell transplantation. Results were compared with those of 50 comparable patients who refused or were unable to receive intensive treatment for socioeconomic reasons. Following high-dose therapy, the rate of CR increased from 6 to 37%, with median survival prolonged by 10 months. Survival of 21 patients with disease converted from PR to CR (median 8.3 years) was significantly longer than that of similarly-treated patients who remained in PR (median 5.0 years). CR of myeloma represents the major surrogate marker of long survival and the primary goal of myeloablative treatment for patients in PR. Twelve of 18 patients with rapid reduction of myeloma protein (T1/2 < 0.5 months), and myeloma protein reduction to <1.0 g/dl after primary therapy achieved CR (67%), identifying pretransplant features favorable to intensive therapy. Among 35 patients with slower reduction or higher residual myeloma protein, CR occurred in eight patients (23%) (P < 0.01), for whom other treatments should be considered. The kinetics of response to initial therapy should be considered in selecting patients more likely to achieve CR and consequent long survival after intensive treatment.

Background: Thalidomide is effective in approximately 30% of patients with refractory multiple myeloma. Dexamethasone is active in 25% of patients with disease resistant to alkylating agents. We investigated the combination of thalidomide with dexamethasone as salvage treatment for heavily pretreated patients with multiple myeloma, in order to assess its efficacy and toxicity. Patients and methods: Forty-four patients with refractory myeloma were treated with thalidomide, 200 mg p.o. daily at bedtime, with dose escalation to 400 mg after 14 days, and dexamethasone, which was administered intermittently at a dose of 20 mg/m2 p.o. daily for four days on day 1-4, 9-12, 17-20, followed by monthly dexamethasone for four days. Patients' median age was 67 years. All patients were resistant to standard chemotherapy, 77% were resistant to dexamethasone-based regimens and 32% had previously received high-dose therapy. Results: On an intention-to-treat basis twenty-four patients (55%) achieved a partial response with a median time to response of 1.3 months. The thalidomide and dexamethasone combination was equally effective in patients with or without prior resistance to dexamethasone-based regimens and in patients with or without prior high-dose therapy. Toxicities were mild or moderate and consisted primarily of constipation, morning somnolence, tremor, xerostomia and peripheral neuropathy. The median time to progression for responding patients is expected to exceed 10 months and the median survival for all patients is 12.6 months. Conclusions: The combination of thalidomide with dexamethasone appears active in patients with refractory multiple myeloma. If this activity is confirmed, further studies of this combination as second-line treatment for patients resistant to conventional chemotherapy, and as primary treatment for patients with active myeloma, should be considered.

The study was designed to evaluate the efficacy and safety of an intensive, tri-alkylator conditioning regimen, consisting of thiotepa, busulfan and cyclophosphamide (TBC), prior to autologous hematopoietic cell transplantation in patients with multiple myeloma (MM) and to analyze factors associated with outcome. One hundred and twenty patients with MM received high-dose chemotherapy with TBC followed by autologous bone marrow (n = 24) or peripheral blood stem cell (PBSC) transplantation (n = 96). Fifty-four patients had chemosensitive disease and 66 had refractory disease at the time of transplantation. The overall response rate was 81% and the complete remission (CR) rate was 26%. Patients with chemosensitive disease had a CR rate of 52% vs 5% for patients with refractory disease. Multivariable analysis determined disease status at transplant as the factor most likely associated with long survival. Estimated median survival was 48, 35 and 9 months for patients with chemosensitive, primary refractory or disease in refractory relapse, respectively. Short interval from diagnosis to transplant among patients with primary refractory disease and younger age were also favorable prognostic factors for survival. Patients with refractory disease pre-transplant who achieved remission criteria rapidly after treatment had a worse outcome than the slow responders. Treatment-related mortality with the introduction of PBSC and better supportive care was 4.8%. In conclusion, TBC is an effective and relatively well-tolerated intensive conditioning regimen in patients with MM. A more favorable outcome was observed in patients with chemosensitive disease and with early treatment for primary refractory disease. TBC merits further study in these subgroups and comparison with alternative regimens in prospective studies is warranted.

Purpose: We performed a prospective phase II study to assess the activity of thalidomide in patients with Waldenstrom's macroglobulinemia (WM). Patients and Methods: Twenty patients with WM were treated with thalidomide at a starting dose of 200 mg daily with dose escalation in 200-mg increments every 14 days as tolerated to a maximum of 600 mg. All patients were symptomatic, their median age was 74 years, and 10 patients were previously untreated. Results: On an intent-to-treat basis, five (25%) of 20 patients achieved a partial response after treatment. Responses occurred in three of 10 previously untreated and in two of 10 pretreated patients. None of the patients treated during refractory relapse or with disease duration exceeding 2 years responded to thalidomide. Time to response was short, ranging between 0.8 months to 2.8 months. Adverse effects were common but reversible and consisted primarily of constipation, somnolence, fatigue, and mood changes. The daily dose of thalidomide was escalated to 600 mg in only five patients (25%), and in seven patients (35%), this agent was discontinued within 2 months because of intolerance. Conclusion: Our data indicate that thalidomide has activity in WM but only low doses were tolerated in this elderly patient population. Confirmatory studies as well as studies that will combine thalidomide with chemotherapy or with rituximab may be relevant. © 2001 by American Society of Clinical Oncology.

Purpose: The aim of the study was to evaluate the efficacy and safety of the combination of gemcitabine and ifosfamide as a second-line treatment for advanced urothelial cancer. Patients and methods: Thirty-four patients with metastatic urothelial cancer previously treated with cisplatin (CDDP)/ carboplatin (CBDCA) and/or taxanes-based chemotherapy were studied. Gemcitabine was administered at a dose of 800 mg/m2 on days 1 and 8 and ifosfamide at a dose of 2 g/m2 on days 1 and 8 with adequate amount of Mesna, every three weeks. Hematopoietic growth factors were given between days 3 to 5 and 12 to 16 to maintain the treatment schedule. Results: On an intent to treat basis, there was one complete response (CR) (3%) (95% confidence interval (95% CI): 0% to 10%) and six partial responses (PR) (18%) (95% CI: 7% to 34%), inducing an objective respo̊nse rate (RR) of 21% (95% CI: 9% to 38%); 12 (35%) patients achieved a stable disease (SD) and 15 (44%) a progressive disease (PD). The median time to tumor progression (TTP) was four months (range, 0.52 to 21.6 months) and the median survival nine months (range 0.52 to 28 months). This regimen also provided the opportunity for symptomatic improvement of pain, dysuria, haematuria and leg oedema. Grade 3-4 neutropenia was experienced by 9 (27%) patients, grade 3-4 anemia by 6 (18%) and grade 3-4 thrombocytopenia by 4 (12%). Six patients were hospitalized due to febrile neutropenia. Despite the prophylactic use of hematopoietic growth factors, 8 (23.5%) patients required dose reduction due to myelosuppression. Grade 3 alopecia occurred in 14 (41%) patients, grade 3-4 nausea in 1 (3%), grade 2 fever in 3 (9%), grade 2-3 diarrhea in 2 (6%) and grade 2 allergic reaction in 1 (3%). Conclusion: We conclude that the combination of gemcitabine and ifosfamide is an active salvage regimen for the treatment of urothelial cancer and that the treatment also has a tolerable toxicity profile; it warrants further investigation in combination with CDDP in chemotherapy-naïve patients.

We evaluated the efficacy and tolerance of the combination of docetaxel and vinorelbine as first line treatment in metastatic breast cancer (MBC). These agents have different mechanisms of action and both are active in advanced breast cancer. Thirty-nine chemotherapy-naive for metastatic disease patients were treated on an out-patient basis with vinorelbine 20mg/m2 i.v. on days 1 and 8 and docetaxel 85mg/m2 i.v. on day 8, every 3 weeks. Twenty-one (53.8%) patients had locoregional disease, 30 (76.9%) had distant metastases and 20 (51.3%) had visceral metastases. The intent-to-treat objective response rate (RR) was 48.75% (19 out of 39 patients; 95% confidence interval (CI), 32.4% to 65.2%). Four patients (10.25%) achieved a complete response (CR) (95% CI, 2.9% to 24.2%) and 15 (38.5%) a partial response (PR) (95% CI, 23.4% to 55.4%). The median duration of response was 4 months, the median time to progression (TTP) was 6 months and the median survival-time was 11.3 months. Grade 3 and/or 4 (3/4) anemia and thrombocytopenia occurred in 7.7% and 5.1% of patients, respectively. Twelve (30.7%) patients developed grade 3/4 neutropenia and 7 (17.9 %) were complicated with fever. Grade 3/4 diarrhea, nausea-vomiting, fatigue and constipation were not a problem. Alopecia was universal. Grade 3/4 neurotoxicity was evident in 2.6% of patients. None of the patients developed allergic reaction or fluid retention. There was one treatment-related death due to grade 4 neutropenia and sepsis. Conclusion: This combination of docetaxel and vinorelbine, a non-anthracycline-containing regimen, is a moderately effective regimen for the treatment of chemotherapy-naive breast cancer patients with metastases, causing only mild to moderate toxicity.

Testicular non-Hodgkin's lymphoma is an uncommon disease and its outcome following chemotherapy and/or radiotherapy has been variable. A retrospective analysis was performed on 26 patients with primary testicular lymphoma treated predominantly with anthracycline-based chemotherapy between 1984 and 1999. The patients' median age was 60 years (range 19-82 years) with 17 (65.4%) patients being older than 60 years. Four (15.4%) patients had constitutional B symptoms. There were 11 (42.3%) patients with high grade lymphoma, 12 (46.2%) with intermediate grade, 1 (3.8%) with low grade and 2 (7.7%) were not classified. According to the Ann-Anbor staging system, 18 patients (69.2%) had early (stage I/II) and 8 (30.8%) advanced (stage III/IV) disease. Chemotherapy was administered to 24 patients including 22 patients who received anthracycline-based chemotherapy. Two stage IEA patients were treated with orchidectomy and adjuvant radiotherapy to the regional lymph nodes without systemic chemotherapy. Chemotherapy alone resulted in a complete remission (CR) in 14 (58.3%) of 24 patients and partial remission in 1 (4.2%), amounting to an overall response rate (RR) of 62.5%. Of the 5 stage I patients who had chemotherapy on an adjuvant basis, 4 (80%) had CR/no evidence of disease. Of the 11 stage II patients, 8 (72.7%) achieved CR and 1 (9.1%) PR (overall RR of 81.8%). CR was obtained in 2 (25%) of 8 stage III/IV patients. Both patients remain disease free for 26 and 65 months. Excluding the 5 stage I patients, chemotherapy resulted in a CR in 10/19 (52.6%) patients and a PR in 1/19 (5.2%), inducing an overall RR of 57.8%. The mean duration of response was 75 months (range 8-145.5+ months). After a median follow-up of 87 months (range 0.13-145.5+ months) the median survival time was 31 months (range 0.13-145.5+ months) and the median time to progression (TTP) 17 months (range 0.13-145.5+ months). The median TTP was significantly higher in early disease compared to that of advanced disease (52 vs. 3 months, p = 0.02). Of the 3 patients who relapsed following disease-free status, CNS involvement occurred in 2 stage II patients and contralateral testis involvement in 1 stage IEA, respectively. The latter remained disease free for 2 years following orchidectomy alone. The other 2 patients who relapsed did not respond to salvage chemotherapy and died. There was no significant relationship between the values of LDH and β2-microglobulin with the outcome except for ESR which was significantly related with the CR (p = 0.005) or RR (p = 0.005). In conclusion, patients with primary testicular lymphoma have a poor outcome, despite the treatment with anthracycline-containing regimens. Treatment with anthracycline-based chemotherapy is recommended in patients at early stages. In advanced disease, more intensive or investigational regimens should be considered. Because the relapse rate in the CNS and contralateral testis is quite high in most studies, prophylactic CNS treatment and radiotherapy to the other testis should be included in the management of testicular lymphoma. Copyright (C) 2000 S. Karger AG, Basel.

Gemcitabine plus paclitaxel and paclitaxel plus carboplatin are active and well tolerated in patients with advanced non-small cell lung cancer, showing similar rates of response and survival. The Hellenic Cooperative Oncology Group conducted a randomized phase III trial comparing gemcitabine plus paclitaxel with paclitaxel plus carboplatin. Patients were randomly assigned to two groups. Group A received paclitaxel 200 mg/m2 plus carboplatin (area under the curve = 6) on day I. Group B received paclitaxel in identical fashion to group A plus gemcitabine 1,000 mg/m2 on days 1 and 8 every 3 weeks. A minimum of two cycles and a maximum of six cycles was allowed. To date, 127 eligible patients (63 in group A and 64 in group B) have been randomized; the median follow-up time is 4.6 months. Preliminary results suggest that both combinations can be given in full doses and are well tolerated. Grade 3/4 neutropenia was mild but more prominent in group A (10% v 3%, respectively) while thrombocytopenia was not significant for either group. Moreover, severe neurotoxicity, hepatotoxicity, or cardiac toxicity has not been observed in the vast majority of patients in either group. Although patients in group B experienced higher response rates (37.5%) than those in group A (21.8%), the difference between the groups was not statistically significant. Definite conclusions about this study cannot be made until more data are available. Copyright (C) 2000 by W.B. Saunders Company.

We report a patient with a history of orchiectomy for Leydig cell tumor of the testis who developed Cushing syndrome. This syndrome was due to ectopic production of cortisol and was the primary feature of tumor recurrence. (C) 2000 Elsevier Science Inc.

Background: The prognosis of platinum resistant ovarian cancer is very poor and the treatment of choice has not been clearly defined. Patients and methods: We conducted a phase II study with the combination of ifosfamide i.v. at 2.25 g/m2 (days 1, 2) and etoposide per os at 100 mg daily (days 1- 10) every four weeks. To be eligible for the study patients had to be resistant to platinum and paclitaxel pretreated. Results: Forty-one patients entered the study. The median interval from the previous chemotherapy was 3.9 months. The median number of previous chemotherapeutic regimens was 2. Severe toxicities included neutropenia (41% of patients), leukopenia (29%) and thrombocytopenia (13%). Thirty-five patients are assessable for response. Nine patients responded (22% of the eligible, 26% of the assessable), four of them demonstrated complete response to chemotherapy (10% and 12%, respectively), while three patients demonstrated stabilization of their progressive disease. After a median follow-up of 18 months, time to progression is 3 months (range 0.9-14.4), duration of response is 9 months (2.5-11) and median survival is 13 months (2.5-37.4+). Conclusions: The combination of ifosfamide with oral etoposide appears to have significant but manageable toxicity and encouraging efficacy in platinum resistant ovarian cancer.

Objectives. Both paclitaxel and cisplatin have moderate activity in patients with metastatic or recurrent carcinoma of the endometrium, and the combination of these two agents has shown activity in a variety of solid tumors. We administered this combination to patients with metastatic or recurrent carcinoma of the endometrium to evaluate its activity and to define its toxicity. Methods. Twenty-four consecutive patients were treated on an outpatient basis with paclitaxel 175 mg/m2 administered intravenously over a 3-h period followed by cisplatin 75 mg/m2 administered intravenously with granulocyte colony-stimulating factor (G-CSF) support. The chemotherapy was repeated every 3 weeks for a maximum of six courses. Results. Sixteen patients (67%; 95% confidence interval, 4584%) achieved an objective response, including seven complete responses and nine partial responses. The median duration of response was 7 months, and the median times to progression and survival for all patients were 8.4 and 17.6 months, respectively. Some degree of neurotoxicity occurred in 44% of patients. Grade 3 or 4 toxicity included granulocytopenia in 22% of patients and peripheral neuropathy in 9%. Conclusion. The combination of paclitaxel with cisplatin with G-CSF support appears active in patients with metastatic or recurrent carcinoma of the endometrium. The significant incidence of neurotoxicity is of concern and alternative methods of administration of the two agents could be evaluated. (C) 2000 Academic Press.

A 52-year-old dentist with kappa light chain multiple myeloma relapsed 6 months after 180 mg/m2 melphalan and an autograft. A partial remission had been attained after the autograft. Relapse occurred while he was on dexamethasone maintenance therapy. Chemotherapy was not an option due to low blood counts. Thalidomide was administered at relatively high doses (escalated up to 700 mg daily and continued for 4 months). There was a prompt decline in urine protein from 6067 mg/day to 2177 mg/day within a month. The response continued to improve with achievement of near-complete remission within 6 months and a decline in urine protein to 413 mg/day. Subsequently, grade 3 neutropenia and peripheral neuropathy required dose reduction to 200 mg/day. Disease activity parameters continued to improve on the lower dose of thalidomide. Nine months after starting thalidomide, the patient is in near-complete remission, enjoys an excellent quality of life, and has returned to work. We conclude that thalidomide can effectively control myeloma relapsing after high-dose chemotherapy, and may be especially useful in resistant cases or those unable to tolerate further chemotherapy.

Purpose: To review the clinical features, complications, and treatment of Waldenstrom's macroglobulinemia, a low-grade lymphoproliferative disorder that produces monoclonal immunoglobulin (Ig) M. Methods: A review of published reports was facilitated by the use of a MEDLINE computer search and by manual search of the Index Medicus. Results: The clinical manifestations associated with Waldenstrom's macroglobulinemia can be classified according to those related to direct tumor infiltration, to the amount and specific properties of circulating IgM, and to the deposition of IgM in various tissues. Asymptomatic patients should be followed without treatment. For symptomatic patients, standard treatment consists primarily of oral chlorambucil; nucleoside analogs, such as fludarabine and cladribine, are effective in one third of previously treated patients and in up to 80% of previously untreated patients. Preliminary evidence suggests that anti-CD20 monoclonal antibody may be active in about 30% of previously treated patients and that high-dose therapy with autologous stem-cell rescue is effective in most patients, including some with resistance to nucleoside analogs. Conclusion: Waldenstrom's macroglobulinemia has a wide clinical spectrum that practicing physicians need to recognize early to reach the correct diagnosis. When therapy is indicated, oral chlorambucil is the standard primary treatment, but cladribine or fludarabine can be used when a rapid cytoreduction is desirable. Prospective randomized trials are required to elucidate the impact of nucleoside analogs on patients' survival. A nucleoside analog is the treatment of choice for patients who have been previously treated with an alkylating agent.

Non-African Burkitt's lymphoma is a rare disease among adults without AIDS. Among 1352 Greek adult patients with non-Hodgkin's lymphoma, 24 cases (1.8%) were classified as Burkitt's (BL) or Burkitt-like (BLL) lymphoma. Eleven cases fulfilled the criteria of BL and 13 of BLL. No statistical differences were found in the general characteristics of the two groups at the time of diagnosis. Extranodal involvement was a common finding in both groups and bulky disease (> 10 cm) was observed in almost one half of the patients. The majority of the patients were treated with intensive, although different, protocols. After induction treatment, complete remission (CR) was achieved in 14 patients (60.8%). CR was reached in all cases with stage I-II, while in stage IV the CR rate was 30.4%. The median overall survival was 27 months. The median survival for BL was 13 months compared to 27 months in the BLL group (P = 0.34). The data of the present retrospective analysis, indicated that there were not significant clinical differences between BL and BLL variants. Since BLL is still a non-reproducible category in the REAL classification, all BL variants must be treated uniformly with intensive protocols. (C) 2000 Elsevier Science Ltd.

Background: Gemcitabine and vinorelbine have shown activity in breast cancer. A phase II trial was initiated in order to evaluate the response rate (RR) and time to progression (TTP) of the combination of the two drugs in patients with metastatic breast cancer progressing after first-line taxane-based chemotherapy. Patients and methods: Thirty-one patients were treated with the combination of gemcitabine 1000 mg/m2 days 1 + 8 and vinorelbine 30 mg/m2 days 1 + 8. The cycles were repeated every three weeks. Results: Of 27 evaluable patients 1 (4%, 95% confidence interval (95% CI): 0.1%-19%) achieved complete remission (CR), five (18%; 95% CI: 6%-38%) partial remission (PR), eleven (40%; 95% CI: 22%-61%) stable disease and ten patients progressed. The median duration of response was six months (range 4-10+) and the median duration of disease stabilization was five months (range 2-22+). With a median follow-up of 16 months (range 0.4-22+) the median TTP was 3.5 months (range 0.4-22+) and the median survival was 9.5 months (range 0.4-22+). Grade 3-4 toxicities were granulocytopenia 15 patients (48%), rash 3 patients (10%), neuropathy 1 patient (3%) and thrombocytopenia 1 patient (3%). In conclusion the combination of gemcitabine/vinorelbine in the doses administered in this group of patients had a response rate of 22% and needs to be further evaluated in metastatic breast cancer.

Multiple myeloma (MM) is a B-cell neoplasm characterized by bone marrow infiltration with malignant plasma cells, which synthesize and secrete monoclonal immunoglobulin (Ig) fragments. Despite the considerable progress in the understanding of MM biology, the molecular basis of the disease remains elusive. The initial transformation is thought to occur in a post-germinal center B-lineage cell, carrying a somatically hypermutated Ig heavy chain (IGH) gene. This plasmablastic precursor cell colonizes the bone marrow, propagates clonally and differentiates into a slowly proliferating myeloma cell population, all under the influence of specific cell adhesion molecules and cytokines. Production of interleukin-6 by stromal cells, osteoblasts and, in some cases, neoplastic cells is an essential element of myeloma cell growth, with the cytokine stimulus being delivered intracellularly via the Jack-STAT and ras signaling pathways. While karyotypic changes have been identified in up to 50% of MM patients, recent molecular cytogenetic techniques have revealed chromosomal abnormalities in the vast majority of examined cases. Translocations mostly involve illegal switch rearrangements of the IGH locus with various partner genes (CCND1, FGFR3, c-maf). Such events have been assigned a critical role in MM development. Mutations in coding and regulatory regions, as well as aberrant expression patterns of several oncogenes (c-myc, ras) and tumor suppressor genes (p16, p15) have been reported. Key regulators of programmed cell death (BCL-2, Fas), tumor expansion (metalloproteinases) and drug responsiveness (topoisomerase II alpha) have also been implicated in the pathogenesis of this hematologic malignancy. A tumorigenic role for human herpesvirus 8 (HHV8) was postulated recently, following the detection of viral sequences in bone marrow dendritic cells of MM patients. However, since several research groups were unable to confirm this observation, the role of HHV8 remains unclear. Translation of the advances in MM molecular biology into novel therapeutic strategies is essential in order to improve disease prognosis.

High-dose chemotherapy with autologous peripheral blood progenitor cell (PBPC) support has become a widely used treatment strategy. In order to simplify the procedure, a single very large-volume leukapheresis, programme combined with short-term refrigerated storage of the PBPC was developed. Seventy-two patients suffering from various relatively chemosensitive malignancies received high-dose chemotherapy, consisting of agents with short in vivo half-lives and 24 to 48 hours later, the refrigerated PBPC were reinfused. A single very large-volume apheresis was sufficient to obtain at least 2 × 106/kg CD34+ cells in 58 patients, (81%). and 63% had at least 2.5 × 106 CD34+ cells/kg. Only two patients (3%) were transplanted with less than 1 × 10 CD34+ cells/kg. In three patients (4%) leukupheresis was repeated because of insufficient number of PBPC. The median CD34+ cell count was 3 × 106/kg. A median of 38.5 L blood (range, 21 to 59) was processed, which accounted for a median of 9 × patient's total blood volume. Very large-volume leukapharesis was well tolerated with symptomatic hypocalcemia being the most common (18%) side-effect. The median time to neutrophils >1.5 × 109/L, and to self-supporting platelet COUDI >25 × 109/L, was 10 and 12 days after reinfusion of PBPC graft, respectively. There were no treatment-related deaths. Our results indicate that this simplified approach of PBPC transplantation can be associated with prompt hematologic recovery in most patients and that it can be useful in settings where facilities are limited or for certain diseases where conditioning regimens with short hall-life are appropriate. © 2000 Wiley-Liss, Inc.

Purpose: The combination of paclitaxel and carboplatin has become a widely used regimen in NSCLC due to phase II reports of moderate toxicity, reasonable activity and easy outpatient administration. Purpose of our present prospective study was to evaluate the dose-response relationship of paclitaxel. Patients and methods: Since July 1996, 198 patients with non-operable NSCLC and measurable disease without previous chemotherapy entered the trial. Ninety nine patients (group A) were randomized to receive paclitaxel 175 mg/m2 in three-hour infusion plus carboplatin dosed to an area under the concentration-time curve of 6 every 3 weeks and 99 (group B) to receive the same regimen with paclitaxel increased to 225 mg/m2. Eligibility criteria included WHO performance status 0-2, documented inoperable stage IIIA and IIIB, IV, no brain metastasis, no prior chemotherapy and adequate renal and hepatic function. Patients in both groups were well-matched with baseline disease characteristics. Results: In group A with 90 evaluable patients, the response rate was 25.6%(6 CR, 17 PR) whereas in group B with 88 evaluable patients, the response rate was 31.8% (3 CR, 25 PR), P = 0.733. Median time to progression favored the high-dose paclitaxel (4.3 vs. 6.4 months, P = 0.044). The median survival was 9.5 months for group A versus 11.4 months for group B (P = 0.16). The one-year survival was 37% for group A and 44% for group B (P = 0.35). The best prognostic factor for one-year survival was the response rate (P < 0.0001). With a relative dose intensity of paclitaxel 0.94 in both groups, neurotoxicity (P = 0.025) and leucopenia (P = 0.038) were more pronounced in group B patients. No toxic death was observed. Conclusions: Higher dose paclitaxel prolongs the median time to progression but causes more neurotoxicity and leucopenia. The better response rate, the longer overall and better one-year survival seen with the higher dose of paclitaxel are not statistically significant.

BACKGROUND. The combination of paclitaxel with cisplatin or carboplatin has become the preferred chemotherapy regimen in the treatment of epithelial ovarian carcinoma. Anthracyclines also have activity in this disease. We conducted a Phase II study by using the combination of paclitaxel, cisplatin, and epirubicin for the treatment of advanced ovarian carcinoma. METHODS. Forty consecutive patients with optimally (n = 7) or suboptimally (n = 33) debulked advanced ovarian carcinoma (International Federation of Gynecology and Obstetrics (FIGO) Stage III or IV) were treated with paclitaxel, 135 mg/m2, as a 3-hour intravenous infusion, cisplatin 75 mg/m2 intravenously (i.v.), and epirubicin 50 mg/m2 i.v. every 3 weeks on an outpatient basis. Granulocyte-colony stimulating factor was administered at a dose of 5 μg/kg/day on Days 5-9. RESULTS. Among 28 patients with measurable disease, 24 (86%%) achieved an objective response including 19 complete and 5 partial responses. Among 18 patients who underwent reassessment laparotomy, pathologic complete response was confirmed in 9 patients. At a minimum follow-up of 40 months, the median overall survival had not been reached whereas the median time to progression for all patients was 18.7 months. The median remission duration for women with measurable disease who responded to treatment was 14 months. The treatment was well tolerated without toxic deaths; the most common toxicity was Grade 3/4 neutropenia that occurred in 30% of patients. Significant neuropathy (Grade 2 or higher) developed in only 8% of patients. CONCLUSIONS. The combination of paclitaxel, cisplatin, and epirubicin is a well tolerated outpatient regimen with significant activity in the treatment of advanced epithelial ovarian carcinoma. (C) 2000 American Cancer society.

In order to assess the role of α-interferon or dexamethasone as maintenance therapy for multiple myeloma, 172 consecutive, previously untreated patients with disease of low or intermediate tumor mass received primary therapy with oral melphalan and intermittent, high-dose dexamethasone (MD), repeated monthly. Within 5 months, 84 responding patients were assigned at random to maintenance treatment with α-interferon (3 mU s.c. 3 x weekly) or dexamethasone (20 mg/m2 p.o. each morning for 4 days) repeated monthly until relapse. Upon relapse, MD was resumed for 2 cycles and second responses were maintained with 4-day courses of melphalan-dexamethasone until second relapse. Initial response was achieved in 88 patients (51%) after a median 0.7 month and no more than 3 courses of MD, a frequency of response similar to that observed previously with dexamethasone alone. There were identical median remissions of 10 months with interferon or dexamethasone, both maintenance regimens being associated with infrequent, mild, and reversible side effects. Significantly more patients responded again to resumption of MD after disease relapse to interferon (82%) than to dexamethasone (44%) (P = 0.001). The median remission from randomization to melphalan-resistant second relapse was 32 months for patients maintained initially on interferon compared to 19 months for those on dexamethasone (P = 0.01). These findings supported an advantage for interferon in remission maintenance by increasing the frequency of tumor recontrol with later treatment that included dexamethasone. (C) 2000 Wiley-Liss, Inc.

The importance of insulin-like growth factor 1 (IGF-1) in human serum for the early diagnosis of prostate cancer is controversial. The IGF-1/PSA ratio may improve the performance of prostate specific antigen (PSA) as a prostate cancer marker. IGF-1, along with PSA and free PSA concentration, was measured in the serum of 34 patients with prostate cancer and in 131 patients with benign prostatic hyperplasia (BPH). Although IGF-1 concentration did not significantly differ between the groups, PSA/IGF-1 ratio could clearly distinguish the two groups. In patients with cancer but not in patients with BPH, IGF-1 concentration correlated with PSA and free PSA. The values of PSA and free PSA correlated with each other for both groups. Receivers Operating Curve (ROC) analysis indicated a better sensitivity to specificity ratio for PSA/IGF-1 than for PSA or Free/Total (F/T) PSA.

Most patients with multiple myeloma (MM) present with symptoms, have evidence of generalized disease, and require chemotherapy promptly to reduce the malignant clone. Some patients present with a local symptom from a single plasmacytoma but no myeloma elsewhere. Such patients usually become free of symptoms after local radiotherapy. In patients with MM without symptoms, the diagnosis is made on the basis of screening laboratory tests. In patients with either solitary plasmacytoma of bone or asymptomatic MM, systemic treatment should be deferred until there is evidence of disease progression. (C) 2000 by The American Society of Hematology.

Recent data suggest that thalidomide is active in approximately 30% of patients (pts) with refractory multiple myeloma. Between 7/99 and 7/00 we treated 38 pts with refractory myeloma with thalidomide 200 mg PO q.h.s, increased to 400 mg after two weeks (in absence of severe side effects), and intermittent dexamethasone 40 mg p.o. x 4 days on days 1-4, 9-12, 17-20 followed by monthly dexamethasone (days 1-4). Pts median age was 67 years (49 to 79 years). Immediately prior therapy has consisted of high-dose pulse dexamethasone (21 pts) or VAD (17pts). Twelve pts had previously received an autologous stem cell transplant. Fourteen pts were considered as primary refractory and 24 pts were treated during refractory relapse. Serum b2-microglobulin > 3.0 mg/dl was present in 66% of pts and elevated serum LDH in 26%. Among the 33 patients évaluable for response so far, 17 (52%) have achieved a partial response defined by reductions > 50% of serum monoclonal protein and/or by >75% of urine monoclonal protein. The time to response was short (median: 1.5 months, range 0.5 to 3 months). Side effects included constipation (75%), morning somnolence (54%), tremor (25%), dry skin/rash (18%), headache (14%) and peripheral neuropathy (7%). Our results indicate activity of the combination of thalidomide with dexamethasone in pts with multiple myeloma refractory to dexamethasone-based regimens. Pts accrual and follow up is ongoing in order to define the activity of this combination in pts'subsets and to assess the duration of response.

Among all imaging modalities, magnetic resonance imaging provides the most useful information about the accurate staging of solitary bone plasmacytoma, the prediction of progression of asymptomatic multiple myeloma and the prognosis of symptomatic multiple myeloma. Furthermore, magnetic resonance imaging contributes to the differential diagnosis of compression fractures in patients with myeloma and can be used for assessment of response to treatment.

Preliminary evidence suggests that rituximab, a chimeric antibody that targets CD20+ B cells, may be active in Waldenstrom's macroglobulinemia (WM). In May 1999 we initiated a prospective trial during which patients with WM were treated with rituximab, 375 mg/m2, administered by IV infusion weekly for 4 consecutive weeks. Three months after completion of rituximab, patients without evidence of progressive disease received repeat 4-week courses of this agent. Twelve patients have been treated so far.Eight patients were previously untreated, 2 primary refractory and 2 were treated during resistant relapse. The median age was 77 years (range: 39 to 85 years), hemoglobin was < 10.0 gr/ dl in 5 patients, lymphadenopathy and splenomegaly were present in 6 and 5 patients respectively. After the initial 4-week courses of rituximab responses were as follows: 75% reduction of IgM in 3 patients, 50% reduction of IgM in 2 patients, 25% reduction of IgM in 1 patient, stable disease in 4 patients and progressive disease in 2 patients. At least 50% reduction of IgM was noted in 3 of 8 previously untreated patients and in 2 of 4 pretreated patients. Among the 10 patients eligible for the second 4-week course of rituximab, 5 patients are évaluable so far: a 25% decrease of IgM was noted in two patients with stable disease after the first course of rituximab. Disappearance or significant reduction of lymphadenopathy or splenomegaly and of bone marrow lymphocytosis occurred in all responding patients. Treatment with rituximab was well tolerated: 3 patients developed grade 1,2 rigors and fever and 2 patients developed flushing. Our prospective study indicate that rituximab is an active and well torelated agent for the treatment of WM.

Five cases of acute neutropenic enterocolitis complicating taxane-based chemotherapy are described. During a 34-month period, our department administered 4,600 courses of taxane-based (paclitaxel and docetaxel) chemotherapy to 800 cancer patients. Seven to 10 days postchemotherapy in five patients (0.1% of the given courses), neutropenic fever, abdominal pain, rebound tenderness, and grade II-IV diarrhea (bloody in two cases) developed. Two patients had oral candidiasis, and in two others septic shock developed. Computed tomography scans of the abdomen revealed in all patients thickening of the colon wall and pericolic edema, and a pericolic abscess was revealed in three of them. Both clinical and radiologic findings supported the diagnosis of acute neutropenic enterocolitis. All patients were successfully treated with broad-spectrum antibiotics and recombinant human granulocyte colony-stimulating factor. In conclusion, acute neutropenic enterocolitis is a severe complication of taxane-based chemotherapy. Early diagnosis and appropriate conservative treatment leads to complete recovery. Although rare, this infection is less often associated with other chemotherapeutic regimens.

Thalidomide is an active agent in patients with refractory multiple myeloma. Based on these data we performed a phase II study in order to evaluate the activity of thalidomide in Waldenstrom's macroglobulinemia (WM). Thalidomide was administered on a doseescalating schedule of 200 mg daily p.o. x 14 days with dose escalation by 200 mg every two weeks to a maximum dose of 600 mg. Twenty patients were treated with a median age of 74 years (range: 48 to 85 years). Hemoglobin was < 10.0 gr/dl in 5 patients, serum monoclonal IgM was >3.0 gr in 9 patients and lymphadenopathy and splenomegaly were present in 7 and 10 patients respectively. Ten patients were previously untreated, 1 was relapsing off treatment, 5 were primary refractory and 4 were treated during refractory relapse. Five patients (25%) achieved at least 50% reduction of serum monoclonal IgM and at least 50% reduction of tumor at all involved sites. At least 25% reduction of IgM was noted in all eventual responders within 4 weeks of thalidomide treatment. Responses occurred in 3 of 10 previoulsy untreated patients and in 2 of 10 pretreated patients. One responding patient with artial fibrillation died of an embolie cerebral accident 4 months after achieving a response and the other responding patients remain without progression for 2+ months to 12 + months. Some degree of toxicity was observed in almost all patients. Grade 2 or 3 toxicities included constipation in 6 patients, somnolence in 3 patients, tremor in 2 patients and neuropathy in 2 patients. This explained the inability to reach the targeted dose of thalidomide 600 mg p.o. QD in all but 4 patients; the median daily dose of this agent was 200 mg. We conclude that thalidomide has moderate activity in WM. A relatively low median daily dose could be administered to this elderly patient population.

Bone metastases from solid primary tumors, as well as multiple myeloma and secondary lymphoma may all present with bone lesions and associated soft-tissue masses on magnetic resonance images of the spine. In bone metastases and myeloma, the cortex of the affected bone is usually destroyed and a bulging contour is observed at the site of extraosseous spread. In cases of lymphomatous involvement of the bone marrow, however, we have observed that spread to the extraosseous soft-tissues occurs without alteration of the shape or contour of the affected bone. In order to assess whether this pattern of spread is indeed suggestive or even diagnostic of lymphoma of the bone marrow, we reviewed spinal bone marrow MR images of 66 patients, with bone metastases from solid primary tumors (33 patients), multiple myeloma (20 patients) and stage IV lymphoma with bone marrow involvement (13 patients), who had bone lesions and contiguous soft-tissue masses. If tumor was present on either side of the bony cortex but the contour of the affected bone was preserved, a 'wrap-around' sign was diagnosed. A 'wrap-around' sign was found in 12 of the 13 patients with lymphoma but in none of the patients with metastases or myeloma. On MR images of the bone marrow, the demonstration of tumor spread beyond the bony cortex without disruption of the outline of the diseased bone may favor the diagnosis of lymphoma more than that of metastases or multiple myeloma.

Cutaneous metastasis from intraabdominal carcinoma is relatively rare. When it is present it is usually located in the skin overlying the neoplasm. Carcinoma of the uterus metastatic to the skin accounts for 9% of all cutaneous metastases. Distant metastasis is extremely rare. Such a metastasis to the skin of the big toe of the lower limb is presented.

Purpose: To evaluate the tolerance and efficacy of the combination of docetaxel and gemcitabine in patients with advanced non-small-cell lung cancer (NSCLC). Patients and Methods: Fifty-one chemotherapy-naive patients with NSCLC were treated with gemcitabine 900 mg/m2 intravenously on days 1 and 8 and docetaxel 100 mg/m2 intravenously on day 8 with granulocyte colony-stimulating factor (150 μg/m2, subcutaneously) support from day 9 to day 15. Treatment was repeated every 3 weeks. Results: The patients' median age was 64 years. The World Health Organization performance status was 0 to 1 in 39 patients and 2 in 12 patients. Fifteen patients (29%) had stage IIIB disease, and 36 (71%) had stage IV; histology was mainly squamous cell carcinoma (59%). A partial response was achieved in 19 patients (37.5%; 95% confidence interval, 24% to 50%); stable disease and progressive disease were each observed in 16 patients (31.4%). The median duration of response and the time to tumor progression were 5 and 6 months, respectively. The median survival was 13 months, and the actuarial 1-year survival was 50.7%. Grade 4 anemia and thrombocytopenia were rare (2%). Four patients (8%) developed grade 3 or 4 neutropenia, and all were complicated with fever; there was no treatment-related death. Grade 3 or 4 diarrhea occurred in three patients (6%), grade 2 or 3 neurotoxicity in four patients (8%), grade 2 or 3 asthenia in 10 patients (20%), and grade 2 or 3 edema in 10 patients (20%). Conclusion: The combination of docetaxel/gemcitabine is well tolerated, can be used for outpatients, and is active for the treatment of advanced NSCLC. This treatment merits further comparison with other cisplatin- or carboplatin-based combinations.

Purpose: To define the disease course, therapeutic strategies, patterns and rates of relapse and causes of death for patients with Hodgkin's disease with lymphocyte predominance (LPHD) and to assess prognostic factors including nodular and diffuse histologic patterns. Patients and Methods: The records of all previously untreated patients with LPHD who received initial treatment at the University of Texas M.D. Anderson Cancer Center (UTMDACC) from 1960 through 1992 were reviewed. Clinical and histopathologic characteristics, specifically nodular and diffuse LPHI), and treatment groups were assessed by overall and relapse-free survival, patterns of relapse, and causes of death. Results: Of 70 patients, 58 (83%) had nodular LPHD and 12 (17%) had a diffuse pattern: clinical characteristics were similar between the two subtypes. The median age of all patients was 25 years, 79% were male, 96% presented with stage I or II disease and 93% were free of B symptoms. Laparotomy (23 patients) failed to upstage any patient with a negative lymphogram. With a median follow-up of 12.3 years for alive patients, 19 (27%) patients have relapsed. All 3 relapses among the patients with diffuse subtype occurred within 3 years while 9 of 16 relapses occurred after 5 years with nodular subtype. However, we did not detect any statistically significant difference in relapse free survival or survival between the subtypes in our patient population. There was some suggestion that patients aged 40 and older experienced shorter survival; no other pretreatment characteristics were noted to be associated with relapse free survival or survival. Though there were no relapses within the radiation fields, no effect of extent of radiation therapy on relapse rate was observed. Thirteen (19%) patients have died, 6 (8.6%) of whom succumbed to LPHD. Two patients developed diffuse large cell lymphoma. Conclusions: Patients with LPHD usually present with localized and asymptomatic disease. Laparotomy is unnecessary if the lymphogram is negative. Nodular histology occurred in the majority of patients. Though all relapses from diffuse subtype occurred within 3 years in contrast to some late relapses observed for nodular subtype, there was no statistically significant difference in relapse free survival or survival between the subtypes. The extent of irradiation had no effect on relapse free survival or survival. We could not find any evidence that LPHD should be treated any different from the classical Hodgkin's disease at this point despite suggestions that it be classified as a non- Hodgkin's B-cell lymphoma.

Retrorectal-cyst hamartomas (RCH) are rare developmental tail-gut cystic tumours of the retrorectal space, which occasionally undergo malignant transformation. We describe the magnetic resonance imaging (MRI) findings in two patients with RCH and in a third patient with unclassified sarcoma arising from a RCH. The RCH were hypointense or hyperintense on T1-weighted images and hyperintense on T2-weighted images; they did not enhance and they contained multiple septations. A solid component in the periphery of one cyst was markedly hypointense on T2-weighted images in keeping with fibrous material. The sarcoma arising from the wall of the RCH enhanced and was of intermediate signal intensity on all sequences. MR may help establish the diagnosis of RCH if an unenhanced cystic tumour is discovered in the retrorectal space and it can help detect those rare cases of malignant transformation of these developmental tumours.

In recent years, several cancer patients who developed neutropenic fever were effectively treated on an outpatient basis with either intravenous or oral antibiotics. This approach is associated with reduced cost and improved patient convenience. However, the appropriate antibiotic regimen and the role of growth factors have not been established yet. In order to address these issues we performed a nonrandomized phase II study to assess the feasibility and efficacy of an oral antibiotic regimen in combination with granulocyte colony-stimulating factor (G-CSF) for the outpatient treatment of cancer patients with low-risk neutropenic fever. In 50 patients with solid tumors or lymphoma, 60 episodes of neutropenic fever were treated with the combination of oral ofloxacin 400 mg twice a day, oral amoxicillin 1 g 3 times a day and G-CSF 5 μg/kg/day subcutaneously. Patients receiving G-CSF prophylaxis were eligible for our study. Oral antibiotics were administered for at least 5 days and G-CSF was continued until resolution of neutropenia. Our patients were ambulatory, hemodynamically stable, and without significant comorbidity. Our combination was successful in 57 episodes (95%) with a median time for fever resolution of 3 days (range: 1-5 days). There was no significant toxicity associated with the antibiotic regimen with the exception of one case of reversible renal impairment. The role of G-CSF in the success of our antibiotic treatment is highly questionable since one half of our patients developed fever while on G-CSF prophylaxis. The combination of oral ofloxacin and amoxicillin with G-CSF is highly effective for the outpatient treatment of cancer patients who develop uncomplicated febrile neutropenia. The relative contribution of G-CSF needs clarification with a prospective randomized study.

Purpose: Both paclitaxel and cisplatin have moderate activity in patients with metastatic or recurrent cancer of the cervix, and the combination of these two agents has shown activity and possible synergism in a variety of solid tumors. We administered this combination to patients with metastatic or recurrent cervical cancer to evaluate its activity. Patients and Methods: Thirty-four consecutive patients were treated on an outpatient basis with paclitaxel 175 mg/m2 administered intravenously over a 3-hour period followed by cisplatin 75 mg/m2 administered intravenously with granulocyte colony-stimulating factor support. The chemotherapy was administered every 3 weeks for a maximum of six courses. Results: Sixteen patients (47%; 95% confidence interval, 30% to 65%) achieved an objective response, including five complete responses and 11 partial responses. Responses occurred in 28% of patients with disease within the radiation field only and in 57% of patients with disease involving other sites. The median duration of response was 5.5 months, and the median times to progression and survival for all patients were 5 and 9 months, respectively. Grade 3 or 4 toxicities included anemia in 18% of patients and granulocytopenia in 15% of patients. Fifty-three percent of patients developed some degree of neurotoxicity; 21% of cases were grade 2 or worse. Conclusion: The combination of paclitaxel with cisplatin seems relatively well tolerated and moderately active in patients with metastatic or recurrent cervical cancer. The significant incidence of neurotoxicity is of concern, and alternative methods of administration of the two agents could be evaluated. Then, further study of this combination, alone or with the addition of other active agents, is warranted.

OBJECTIVE: To evaluate the part played by several parameters in the prognosis of patients with endometrial carcinoma. STUDY DESIGN: Eighty imprint smears from fresh endometrial tumor specimens were studied immunocytochemically for the expression of p53, bcl-2 and epidermal growth factor receptor. Also, the presence of estrogen receptor (ER) and progesterone receptor (PR) in the tumor tissue was measured. The data obtained were related to survival, and associations were sought between the parameters studied. RESULTS: Strong associations were found between advanced stage, high grade, lymph node metastases at diagnosis, nonendometrioid histology and p53 expression with poor survival. Bcl-2 expression was associated with good five-year survival. ER expression was associated marginally with good five-year survival, but PR expression was not. A strong association was found between p53 and advanced disease, stage and lymph node metastases at diagnosis. An association between EGFR positivity and survival was not found. CONCLUSION: p53 Expression of uterine tumors is an independent and strong indicator of poor prognosis. Even patients with stage I and II disease at surgery who have p53-positive tumors must be considered at high risk.

Purpose: To determine the efficacy and tolerance of single-agent docetaxel and granulocyte colony-stimulating factor in patients with advanced pancreatic cancer. Patients and Methods: Thirty-three chemotherapy-naive patients (median age, 65 years) with histologically confirmed pancreatic cancer were treated, after appropriate premedication, with docetaxel (100 mg/m2) and granulocyte colony-stimulating factor (150 μg/m2/d subcutaneously days 2 through 10) every 3 weeks. World Health Organization performance status was 0 to 1 in 28 patients (85%) and 2 in 5 patients (15%). Twenty-nine patients had stage III and IV disease. Results: One complete response (3%) and one partial response (3%) were observed for an overall response rate of 6% (95% confidence interval, 2.1% to 14.2%). Nineteen patients (58%) had stable disease and 12 (36%) had progressive disease. The duration of the two objective responses was 10 and 28 weeks, and the median time to tumor progression was 20 weeks. The median overall survival was 36 weeks. The actuarial 1-year survival was 36.4%. The performance status improved in seven of 21 assessable patients (24%) and pain improved in 14 of 21 (67%) assessable patients; five patients (29%) experienced weight gain during treatment. Disease-related asthenia, anorexia, vomiting, and diarrhea improved in 29%, 15%, 67%, and 47% of the assessable patients, respectively. Serum concentrations of CA 19-9 were decreased by more than 50% in seven patients (35%). Grade 3 and 4 neutropenia occurred in four patients (12%) and eight patients (24%), respectively, with two episodes of febrile neutropenia. There were no treatment-related deaths. Grade 3/4 asthenia occurred in three patients. Conclusion: Although docetaxel has a marginal objective activity in pancreatic cancer, it seems to have an important effect on tumor growth control, conferring a clinical benefit.

Purpose: Both docetaxel and cisplatin have moderate activity in patients with advanced urothelial cancer. We performed a multicenter phase II study in order to assess the efficacy and toxicity of the combination of these two agents in patients with advanced carcinoma of the urothelium. Patients and methods: Sixty-six patients not amenable to curative surgery or irradiation were enrolled onto this cooperative group study and treated on an outpatient basis with docetaxel 75 mg/m2 followed by cisplatin 75 mg/m2, both administered intravenously. Granulocyte-colony stimulating factor was administered subcutaneously at a dose of 5 μg/kg daily from day 5 until resolution of neutropenia. The chemotherapy was administered every three weeks for a maximum of six courses in patients without evidence of progressive disease. Results: Thirty-four of sixty-six patients (52%, 95% confidence interval 40%-64%) demonstrated objective responses, with eight achieving clinical complete responses and twenty-six partial responses. A multivariate logistic regression analysis indicated that the patients most likely to respond were those without lung metastasis and without weight loss before treatment. The median duration of response was 6.1 months and the median times to progression and survival for all patients were 5 and 8 months, respectively. Absence of anemia, of liver metastases and of weight loss correlated with longer survival. Grade ≥3 toxicities included granulocytopenia in 33% of patients, anemia in 14%, diarrhea in 13% and emesis in 7% of patients. Conclusion: The combination of docetaxel and cisplatin appeared relatively well tolerated and moderately active in patients with advanced urothelial cancer. The patients most likely to benefit were those without weight loss and without lung or liver metastases.

A small proportion of patients with plasma cell myeloma have a solitary plasmacytoma of bone. Strict staging criteria, including normal MR imaging studies of the axial skeleton and the long bones and absence of monoclonal plasma cells detected by flow cytometry or PCR, are required for diagnosis. Radiotherapy at a dose of 4500 cGy is required to eradicate the local tumor. Many patients enjoy prolonged disease-free survival, but the incidence of systemic relapse is high. It is expected, however, that if strict diagnostic criteria are applied some patients may be cured. Extramedullary plasmacytoma is an even rarer plasma cell disease which usually occurs in the head and neck area. Careful microscopic and immunohistochemical studies are required for the correct diagnosis, because this disease can be confused with other malignancies, particularly lymphomas. The treatment of choice is radiotherapy which, in cases of head and neck plasmacytomas, should encompass the adjacent lymph nodes. Most patients with extramedullary plasmacytoma can be cured, and fewer than 30% develop a distant failure in the form of multiple myeloma or multiple extramedullary tumors.

Waldenstrom's macroglobulinemia is an unusual low-grade lymphoplasmacytic lymphoma characterized by the production of monoclonal IgM. The clinical manifestations associated with WM can be classified as those related to direct tumor infiltration, by the amount and specific properties of circulating IgM, and by the deposition of IgM in various tissues. Asymptomatic patients should be followed without treatment. The management of the disease relies on the administration of systemic chemotherapy to reduce tumor load and on the application of plasmapheresis to remove circulating IgM. Standard treatment consists of oral chlorambucil, which induces response in at least 50% of patients, resulting in a median survival of approximately 5 years. Nucleoside analogues (cladribine, fludarabine) are effective in most previously untreated patients. These agents are the treatment of choice for patients with disease resistant to alkylating agents. New treatment approaches include high-dose therapy with stem-cell support and administration of monoclonal anti-CD20 antibodies.

Purpose: To evaluate the efficacy and safety of the docetaxel-cisplatin combination in patients with advanced non-small-cell lung cancer (NSCLC). Patients and methods: Chemotherapy-naive patients with histologically confirmed, measurable stage IIIB or IV NSCLC, a World Health Organization (WHO) performance status of 0-2 and adequate bone marrow, renal, hepatic and cardiac function were eligible for the study. Patients received docetaxel (100 mg/m2) as an one-hour infusion on day 1 and cisplatin (80 mg/m2) as a 30-min infusion with appropriate hydration on day 2. Granulocyte colony- stimulating factor (G-CSF; 150 μg/m2, SC) was given on days 3 to 13. Treatment was repeated every three weeks. Results: Fifty-three patients were enrolled (28 with stage IIIB and 25 with stage IV). One complete and 23 partial responses were observed (overall response rate (OR): 45%; 95% CI: 34,1%-61.8%). The response rate was 57% and 32% in patients with stages IIIB and IV disease (P = NS). The median time to progression was 36 weeks and the median survival 48 weeks; the one-year survival was 48%. Grade 3-4 neutropenia occurred in 23 patients, 15 of whom were hospitalized for neutropenic fever; two patients died of sepsis. Grade 2 neurotoxicity was observed in six patients and grade 3 in five patients; grade 3 fatigue occurred in seven patients, grade 3-4 mucositis in four patients and grade 3- 4 diarrhea in six patients. Mild allergic reactions and oedema were observed in five and four patients, respectively. The median dose intensity was 30 mg/m2/week for docetaxel and 24 mg/m2/week for cisplatin, corresponding to 91% and 89% of the specified protocol doses, respectively. Conclusions: The docetaxel-cisplatin combination is an active regimen in advanced NSCLC, but hematologic toxicity remains high despite the prophylactic use of G-CSF.

Purpose: To determine the efficacy and safety of 21 monthly cycles of pamidronate therapy in patients with advanced multiple myeloma. Patients and Methods: Patients with stage III myeloma and at least one lyric lesion received either placebo or pamidronate 90 mg intravenously administered as a 4-hour infusion monthly for 21 cycles. At study entry, the patients were stratified according to whether they were to receive first-line (stratum 1) or second-line (stratum 2) antimyeloma chemotherapy. Skeletal events (pathologic fracture, radiation or surgery to bone, and spinal cord compression) and hypercalcemia were assessed monthly. Results: The results of the first nine previously reported cycles are extended to 21 cycles. Of the 392 randomized patients, efficacy could be evaluated in 198 who received pamidronate and 179 who received placebo. After 21 cycles, the proportion of patients who developed any skeletal event was lower in the pamidronate-group (P= .015). The mean number of skeletal events per year was less in the pamidronate-group (1.3) than in placebo-treated patients (2.2; P = .008). Although survival was not different between the pamidronate-treated group and placebo patients overall, stratum 2 patients who received pamidronate lived longer than those who received placebo (14 v 21 months, P = .041). Pamidronate was safe and well tolerated during the 21 cycles of therapy. Conclusion: Long-term monthly infusions of pamidronate as an adjunct to chemotherapy are superior to chemotherapy alone in reducing skeletal events in stage III multiple myeloma patients, and may improve the survival of patients on salvage therapy.

Aberrant expression of apoptosis-related genes including the 'cell death suppressor gene' bcl-2, may play an important pathogenetic role in cancer expression by 2-CdA, and or GST would provide a basis for their efficacy in suppressing arthritis by interfering with the upregulation of bcl-2 mRNA in the synovial lining cells (Muller-Laduer et al., 1995). However, the lack of a direct inhibitory effect on the induction of bcl-2 biosynthesis at the relatively high concentrations tested suggests that both GST and 2-CdA exert their beneficial effects in these patients through a bcl-2 independent mechanism.

Purpose. To evaluate the outcome and the prognosis of patients with ovarian germ cell malignancies who were treated with platinum-based chemotherapy immediately after initial surgery. Methods. We conducted a retrospective review of patients with ovarian germ cell tumors who were referred for consideration of treatment to the Departments of Medical Oncology participating in the Hellenic Cooperative Oncology Group. Results. Over a 14-year period 53 patients were included in our study. There were 13 patients with dysgerminoma and 40 patients with nondysgerminomatous tumors. Forty percent of patients underwent complete resection of their tumors. Platinum-based chemotherapy consisted primarily of cisplatin, vinblastine, and bleomycin (PVB) in 9 patients; bleomycin, etoposide, and cisplatin (BEP) in 15 patients; and bleomycin, etoposide, and carboplatin (BEC) in 25 patients. With a median follow-up of 39 months, 5 patients developed progressive disease and died of their tumor and 1 patient died of bleomycin- induced lung toxicity with no evidence of active tumor. The 5-year overall survival was 100% for patients with dysgerminoma and 85% for patients with nondysgerminomatous tumors. Eighty percent of patients with advanced nondysgerminomatous tumors and residual disease after surgery remain disease free. Conclusion. With this study we confirm that patients with ovarian germ cell malignancies have a favorable outcome when treated with platinum-based chemotherapy.

Purpose: To evaluate the activity and toxicity of the combination of paclitaxel given by three-hour infusion, and carboplatin as first- line chemotherapy in patients with advanced breast cancer (ABC). Background: Paclitaxel is an active agent in ABC. Furthermore, our group has shown that the combination of paclitaxel and carboplatin is effective in anthracycline-resistant ABC. Patients and methods: From January 1996 until March 1997, 66 women with ABC were treated with paclitaxel (175 mg/m2) by three-hour infusion followed by carboplatin at an AUC of 6 mg x min/ml every three weeks. The median age of the patients was 56 years (range 28-75). A total of 39 patients had received adjuvant chemotherapy and 22 of them were treated with an anthracycline or mitoxantrone-containing regimen. Results: A total of 324 cycles (median: six) were administered, 273 (85%) of them at full dose. The median number of delivered cycles was six. The median delivered dose intensity (DI) of paclitaxel was 55.1 mg/m2/week (range 30.5-69.3) and the relative DI was 0.95 (range 0.5-1.2). Eight patients (12%, 95% confidence interval (CI): 5%-22%) achieved complete and 28 (42%, 95% CI: 30%-55%) partial responses. Grade 3-4 toxicities included anemia (5%), granulocytopenia (24%), thrombocytopenia, nausea/vomiting and allergic reaction (3% each), myalgias/arthralgias and neurotoxicity (1,5% each). Febrile neutropenia occurred in eight (12%) patients. Alopecia was universal. After a median follow-up of 17.3 (range 0.07- 24.5) months, 48 (72%) patients have demonstrated tumor progression and 24 (36%) have died. Median time to progression was 8.6 (range 0.07- 23+) months and median survival 20.4 (range 0.07-24.5+) months. Conclusions: The combination of paclitaxel and carboplatin has moderate activity in ABC and can be easily delivered on an outpatient basis with manageable toxicity. This regimen may be useful especially in patients to whom anthracyclines or cisplatin administration is precluded because of other concomitant diseases.

In a phase II study, 66 patients with advanced breast cancer (median age 56 years; range, 28 to 75 years) were treated with paclitaxel (Taxol), 175 mg/m2 infused over 3 hours, and carboplatin (Paraplatin), dosed to attain an area under the concentration-time curve (AUC) of 6 mg x min/mL; treatment was repeated every 3 weeks. A total of 38 (58%) patients had received prior adjuvant chemotherapy, 21 with a regimen containing an anthracycline or mitoxantrone (Novantrone). As of May 1997, 295 cycles of paclitaxel- carboplatin have been administered, 248 (84%) at full dose. The relative dose intensity of paclitaxel is 0.9 (range, 0.5 to 1.2). Of the 66 patients, 8 (12%) have achieved a complete response and 27 (41%) a partial response, for a total response rate of 53%. Grade 3 to 4 toxicities have included anemia (5%), leukopenia (25%), thrombocytopenia (5%), nausea/vomiting (7%), myalgias/arthralgias (4%), allergic reaction, neurotoxicity, and infection (2% each). Alopecia has been universal. Median time to progression is 8.9 months; median survival has not yet been reached. We conclude that the combination of paclitaxel and carboplatin has significant activity in advanced breast cancer and can easily be administered on an outpatient basis with manageable toxicity.

The aim of this study was to investigate the expression of bcl-2, p53 oncoproteins, and Ki-67 antigen in a series of transitional cell bladder carcinomas and its relation to the traditional prognostic indicators and patient's survival. One hundred six cases with transitional cell carcinoma (TCC) were examined for detection of bcl-2, p53 proteins, and Ki-67 antigen (MIB1 antibody). Bcl-2 immunohisto-chemical positivity was observed in 52% of TCCs and in 577% of low-grade and 44% of high-grade TCCs. Bcl-2 was also detected in normal urothelium and dysplastic lesions with basal cell expression, showed a significant inverse correlation with overall bcl-2 positivity. The loss of bcl-2 protein expression in higher-stage TCCs was statistically significant (pt = .01). P53 protein was overexpressed in 50% of TCCs and more frequently in invasive and in carcinomas in situ than in superficial TCCs (Pt = .03). In contrast, detection of p53 was not observed in normal and dysplastic urothelium. P53 positivity was related to the degree of differentiation and to the stage of the disease (Pf = .01 and Pt = .03, respectively). Concerning Ki-67 antigen, its expression was found in 57.5% of TCCs. There was a strong overall correlation of Ki-67 with tumor stage (Pt = .002) and grade (Pf = .002). Univariate statistical analysis showed that the expression of p53 and Ki-67 was significantly correlated to poor prognosis (p = .02, P = .02, respectively). On multivariate analysis, none of these markers but only stage and grade were significantly correlated to prognosis (P = .02, respectively). These findings suggest that overexpression of bcl-2 protein may be an early event in tumorigenesis. Tumors with loss of bcl-2 positivity and overexpression of p53 and Ki-67 had an unfavorable prognosis; however, in multivariate analysis, they had no independent prognostic value.

Karyotypic studies of bone marrow were conducted in 79 previously untreated patients with multiple myeloma who received a standard programme of chemotherapy. An abnormal karyotype was observed in 46% of patients, virtually all showing multiple abnormalities consistent with a long period of preclinical clonal evolution. Patients with an abnormal pattern showed various aberrations with hyperdiploidy in 64%, pseudodiploidy in 5% and hypodiploidy in 31%. The number of chromosomes affected ranged from two to 19 (median 10), with at least one trisomy in 83%, one monosomy in 75%, and one translocation in 42% of patients. Lymphoma-like karyotypes were present in 17% of patients with an abnormality but were not associated with atypical clinical features, such as an extramedullary mass, leukaemia, or increased serum lactate dehydrogenase. Monosomy or deletion of chromosome 13 was present in 47% of patients with an abnormal pattern, who lived for a shorter duration (median 10 months) than patients with other abnormalities (median 34 months) or with diploidy (median 35 months). The cause of the short survival of patients with monosomy or deletion of chromosome 13 was not clear, but further studies on the relationship with specific oncogenes are indicated.

Purpose: The standard treatment for patients with muscle-invasive carcinoma of the urinary bladder is radical cystectomy. While radical cystectomy cures many patients with this tumor, almost 50% of them will develop metastatic disease. Adjuvant chemotherapy has been proposed for these patients in an attempt to reduce the probability of relapse and to improve survival. To assess whether adjuvant chemotherapy does benefit patients with muscle-invasive bladder cancer, we reviewed all phase II and III studies published in the English literature over the last 20 years. Methods: A review of all published reports was facilitated by the use of Medline computer search and by manual search of the Index Medicus. Results: Several comparative, nonrandomized studies have indicated that adjuvant chemotherapy may prolong disease-free survival. Four randomized studies have been conducted and all had a suboptimal patient accrual. Three studies used a cisplatin-containing combination chemotherapy and included primarily patients with non-organ-confined transitional-cell carcinoma (TCC) of the bladder. All three studies indicated that adjuvant chemotherapy improve disease-free survival and two of them also showed improvement in event-free survival and overall survival, respectively. Conclusion: Published series have been unable to establish an undisputed benefit of adjuvant chemotherapy over radical cystectomy alone for muscle-invasive bladder cancer. The interpretation of the available data is compromised by several methodologic and statistical problems. Thus, adjuvant chemotherapy cannot be considered as a standard treatment for all patients with muscle-invasive carcinoma of the bladder. Well-designed prospective randomized studies are needed to clarify the rob of adjuvant chemotherapy in this disease. However, outside a protocol setting, there is some evidence that patients with extravesical disease or with lymph node involvement may benefit from adjuvant treatment with cisplatin-based combination chemotherapy. No data support such an approach for patients with muscle-invasive but organ-confined bladder cancer.

Although the combination of paclitaxel with doxorubicin has yielded high response rates in metastatic breast cancer, severe cardiotoxic events have been reported in several patients. The rationale for our study was to evaluate the activity of paclitaxel/doxorubicin combination in patients with this disease but to avoid excessive cardiotoxicity. Therefore, we administered 4 cycles of doxorubicin/paclitaxel followed by 6 cycles of standard cyclophosphamide, methotrexate and 5-fluorouracil (CMF) regimen. Study medication consisted of doxorubicin 60 mg/m2 as a 15-min intravenous infusion followed by paclitaxel 175 mg/m2 as a 3-hour infusion. CMF regimen consisted of cyclophosphamide 600 mg/m2 as 1-hour intravenous infusion followed by methotrexate 40 mg/m2 and 5-fluorouracil 600 mg/m2 bolus injection. The main toxicity of doxorubicin/paclitaxel treatment phase was neutropenia (WHO grade 3/4, 58%), but we observed only one cardiac adverse event. Toxicities of the CMF treatment phase were not significant. Of 24 patients evaluable for response, 2 (8%) had complete responses and 11 (46%) achieved partial response. Ten additional patients (42%) had stable disease. The median time to progression was 12 months and the median overall survival was 18.5 months. The sequential administration of doxorubicin and paclitaxel followed by CMF appeared active and well tolerated in patients with metastatic breast cancer.

Objectives. To evaluate the efficacy and toxicity of single-agent docetaxel in patients with metastatic urothelial carcinoma and impaired renal function. Methods. Eleven consecutive patients previously untreated for metastatic disease with renal impairment (median serum creatinine level of 2.6 mg/dL) were treated with intravenous docetaxel 100 mg/m2 for 1 hour every 21 days. Granulocyte colony-stimulating factor was administered at a dose of 5 μg/kg/day subcutaneously from days 5 to 14. Results. Five of 11 patients achieved a partial response, with time to progression of responding patients ranging from 5 to 22 months or more. The median overall survival rate was 11 months. Renal function improved in 5 of 8 patients with tumor- related renal impairment. Toxicity was primarily hematologic, with 5 patients developing grade 3 or 4 neutropenia; nonhematologic toxicities were manageable. Conclusions. Our preliminary data indicate that single-agent docetaxel therapy may represent an effective therapeutic alternative for patients with advanced urothelial carcinoma and renal insufficiency precluding cisplatin-based combination chemotherapy.

Purpose: We investigated the activity of combination chemotherapy consisting of cisplatin, ifosfamide, methotrexate and vinblastine in patients with metastatic urothelial cancer. Materials and Methods: A total of 32 consecutive patients was treated with 30 mg./m.2 cisplatin on days 1 through 3, 1.5 gm./m.2 ifosfamide with mesna on days 1 through 3, 30 mg./m.2 methotrexate and 3 mg./m.2 vinblastine on day 1 plus 5 μg./kg. granulocyte colony-stimulating factor on days 7 through 11. Courses were repeated every 21 days for a maximum of 6 cycles. Results: Major toxicity was granulocytopenia in 56% of patients, including 11 episodes of granulocytopenic fever. Anemia and thrombocytopenia developed in a third of the cases. No other significant toxicity or treatment related death was noted. An objective response was achieved in 20 patients (62.5%, 95% confidence interval 44 to 79). Median time to progression was 7 months and median survival was 13 months. Conclusions: The cisplatin, ifosfamide, methotrexate and vinblastine regimen appeared active in patients with metastatic urothelial carcinoma. This regimen was associated with significant but manageable hematological toxicity and the incidence of mucositis or renal impairment was low. Prospective randomized studies are needed to assess whether the addition of ifosfamide to other active agents will improve the survival of patients with this disease.

Objective: To evaluate the efficacy and toxicity of the combination of ifosfamide (1.5 g/m2 i.v. on days 1, 2, 3) and paclitaxel (135 mg/m2 i.v. over 3 hours on day 3) with G-CSF (5 μg/kg/d subcutaneously, days 7-11) administered every 3 weeks on an outpatient basis in patients with advanced epithelial ovarian cancer previously treated with platinum-based chemotherapy. Patients and methods: Thirty-five consecutive patients were treated, 12 of whom had previously received two regimens. Twelve of the 35 were defined as platinum-resistant and 23 as potentially platinum-sensitive. Results: Fifteen patients (43%; 95% CI: 26%-61%) achieved objective responses, five of them complete and ten partial. Objective responses occurred in 17% of the platinum-resistant patients and in 57% of those with potentially platinum-sensitive disease. The median duration of response was seven months and the median overall survival 11 months. The treatment was well tolerated and only 15% of the patients developed grade 3 or 4 neutropenia. With the exception of alopecia there were no other grade 3 or 4 toxicities. Conclusions: The combination of ifosfamide and paclitaxel was well tolerated and showed activity in patients with ovarian cancer who had previously undergone platinum-based chemotherapy.

Late relapses of nonseminomatous germ cell tumors of the testicle are unusual. In such cases, chemotherapy is reported to have only modest success and surgery may be the preferred treatment modality. We report a patient who experienced relapse 11 years after the initial diagnosis of advanced testicular cancer and who achieved a sustained complete remission with salvage chemotherapy alone.

Design: Determine the frequency of t(2;5)(p23;q35) in anaplastic large- cell lymphoma (ALCL), non-Hodgkin's lymphoma (NHL), Hodgkin's disease (HD), and lymphomatoid papulosis (LP). Patients and methods: The t(2;5) was detected with a long-range nested polymerase chain reaction (PCR) using 0,5 μg of DNA (60000-80000 cells), 5'-primers from the NPM gene, 3'primers from the ALK gene, agarose electrophoresis, hybridization, and autoradiography. Patients were evaluable if a 3016 base pair amplicon could be generated from tumor DNA with β-globin primers. Results: Amplicons were detected by PCR of genomic DNA from three ALCL cell lines and four primary ALCLs known to t(2;5) positive. DNA from t(2;5)-positive cell lines diluted 104-fold or 105-fold generated amplicons in 100% or 20% of reactions, respectively. Archival tumor DNA from 144 patients was amplifiable by β-globin amplicons in 126 (88%) who are considered evaluable for this study. Twenty-two had ALCL, 69 other NHLs, 30 HD, and five LP. Genomic DNA PCR detected the t(2;5) in 5 of 22 with ALCL (23%, 95% confidence intervals [95% CI] 8%-45%) but not in those with NHLs, HD, or LP. Among ALCLs the t(2;5) was confined to 5 of 20 with nodal presentations (25%, 95% CI 9%-49%), among whom it was seen in 5 of 15 with T- cell or null-cell phenotype (33%, 95% CI 12%62%), in 4 of 11 with age < 40 years (36%, 95% CI 11%-69%), and in 4 of 9 with nodal presentations, T-cell or null-cell phenotype, and age <40 years (44%, 95% CI 14%-79%). Amplicon sizes were different between cell lines and patients, reflecting unique genomic DNA breakpoints, as confirmed by DNA sequencing, and served as an internal control against specimen cross-contamination in the laboratory. Conclusions: Long-range PCR of genomic DNA detects t(2;5) only in ALCL but not in other NHLs, HD, or LP. Long-range PCR may be useful in establishing diagnosis, determining prognosis, and monitoring minimal residual disease in ALCL.

Purpose: To determine the feasibility and toxicity of inducing autologous graft-versus-host disease (GVHD) with cyclosporine in patients with multiple myeloma undergoing autologous stem-cell transplantation. Patients and Methods: Fourteen multiple myeloma patients with a median age of 50 years (range, 41 to 63) were enrolled. The median time from diagnosis to transplant was 651 days (range, 229 to 3,353). Ten patients had primary refractory disease, two were in first remission, and two were responsive to salvage therapy. The preparative regimen consisted of thiotepa, busulfan, and cyclophosphamide. Cyclosporine was administered daily for 28 days after the stem-cell infusion, and the dose was adjusted to maintain whole-blood cyclosporine levels between 50 and 150 ng/dL in the first seven patients (low-level group) and between 150 and 300 ng/dL in the other seven patients (high-level group). Results: All patients achieved neutrophil engraftment a median of 11 days after transplant. Four patients developed ≤ grade 2 hepatic toxicity, six developed ≤ grade 2 nephrotoxicity, and four developed reversible cardiac toxicity. Only one treatment-related death occurred. Cyclosporine was withheld in seven patients for a median of 6 days because of renal and/or liver dysfunction. One patient developed clinical skin GVHD, which responded to corticosteroid therapy. Six patients developed histologic evidence of GVHD without clinical signs of GVHD (subclinical GVHD). The incidence of clinical and subclinical GVHD was similar in both cyclosporine groups. Three of 11 patients assessable for response achieved remissions. Three patients experienced disease progression 80, 160, and 354 days after transplant. Ten patients are alive without progression between 56 and 444 days after transplant. Conclusion: Induction of autologous GVHD by post- transplant cyclosporine is feasible and well tolerated in patients with multiple myeloma.

BACKGROUND. Patients with metastatic carcinoma of the uterine cervix have limited survival. Thus, new chemotherapeutic agents and combinations are needed to improve patient outcome. METHODS. Twenty-seven patients with Stage IV primary or recurrent carcinoma of the uterine cervix were assigned to chemotherapy treatment at 4-week intervals with methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC). The treatment was comprised of methotrexate, 30 mg/m2 administered intravenously (i.v.) on Days 1, 15, and 22; vinblastine, 3 mg/m2 i.v. on Days 2, 15, and 22; doxorubicin, 30 mg/m2 i.v. on Day 2; and cisplatin, 70 mg/m2 i.v. on Day 2. Granulocyte-colony stimulating factor (G-CSF) was given subcutaneously on Days 6-10 at a dose of 5 μg/kg. RESULTS. After a median of 4 cycles (a maximum of 6 in responders), the authors observed objective responses in 14 patients (52%), including 3 complete responses (11%) and 11 partial responses (41%). Median overall survival was 11 months (range, 4-15+ months), and median progression free survival of the responders was 8 months (range, 6-15+ months). Toxicity was acceptable and included neutropenia, alopecia, vomiting, and stomatitis. CONCLUSIONS. MVAC is an active regimen in the treatment of patients with advanced or recurrent carcinoma of the uterine cervix. It produced responses in one-half of the patients in this study, and it can be administered on an outpatient basis. The addition of G-CSF appears to reduce hematologic toxicity.

Because the outcome of patients with primary ovarian non-Hodgkin's lymphoma (NHL) is controversial, we retrospectively analyzed experience with adults seen at the University of Texas M. D. Anderson Cancer Center from 1974 to 1993. Patients were included if at least one ovary was pathologically involved, and if combination chemotherapy was used that must have included doxorubicin for intermediate grade histologies. We identified 15 patients who constituted 0.5% of all untreated NHL and 1.5% of untreated ovarian neoplasms that presented to our institution during this time. One patient refused therapy, leaving 14 assessable for response. Nine patients had intermediate- grade, 5 had highgrade, and none had low-grade NHL. One ovary was involved in 4 patients, and both in 10, in 7 of whom additional sites were involved, including supradiaphragmatic nodes in 2. Four patients had AAS I and 10 had AAS IV. Favorable (0 or 1) and unfavorable (> 1) IPI scores were seen in 5 and 9 patients, respectively. The complete remission rate for all patients was 64%, and 5-year survival and FFS for all assessable patients were 57 and 46%, respectively. We conclude that the complete remission rate and FFS of patients with ovarian NHL treated with appropriate chemotherapy appear to be similar to that of patients with other nodal NHLs. Further work is required to determine prognostic factors in ovarian NHL.

A phase II study of combination paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ)/gemcitabine was conducted in patients with non-small cell lung cancer (NSCLC) who had failed first-line docetaxel- or cisplatin-based chemotherapy. Eligibility criteria included histologically confirmed measurable stage IIIB or IV NSCLC and previous exposure to docetaxel- or cisplatin-based regimens, World Health Organization performance status between 0 and 2, adequate hematologic parameters, and adequate hepatic, renal, and cardiac function. Gemcitabine (900 mg/m2) was given on days 1 and 8 as a 30-minute infusion; paclitaxel (175 mg/m2) was administered on day 8 as a 3-hour infusion after appropriate premedication. Granulocyte colony-stimulating factor (150 microg/m2 subcutaneously) was given on days 9 to 15. Treatment was repeated every 3 weeks until patients experienced disease progression. From October 1995 to December 1996, 26 patients with advanced NSCLC were enrolled (three stage IIIB, 23 stage IV). All 26 patients were assessable for toxicity, and 24 were evaluable for response. Two complete (8%) and five partial (21%) responses were observed, for an overall response rate of 29% (95% confidence interval, 11% to 47%). The median duration of response was 2.5 months and the median survival was 8 months. A median of three courses per patient was administered, and the median interval between courses was 21 days. The median delivered dose was 579 mg/m2/wk gemcitabine and 54.5 mg/m2/wk paclitaxel, corresponding to a relative dose intensity of 0.97 and 0.96, respectively. Grade 3/4 neutropenia occurred in two patients (8%). Grade 3 conjunctivitis occurred in one (4%) patient and grade 2/3 neurotoxicity in eight (31%) patients. Grade 3/4 and grade 2 fatigue occurred in four (15%) and eight (31%) patients, respectively. Other toxicities were mild to moderate. These preliminary results suggest that the paclitaxel/gemcitabine combination is an active and well-tolerated salvage regimen in patients with NSCLC previously treated with docetaxel- or cisplatin-based chemotherapy. The paclitaxel/gemcitabine combination merits further evaluation as first-line treatment.

The diagnostic value of antimyosin scanning in 7 patients with biopsy- proven cardiac amyloidosis was examined in this study. Antimyosin imaging was positive in all amyloid patients, with more intense uptake in patients with heart failure.

Objectives. Estramustine and etoposide have been shown to inhibit the growth of prostate cancer cells in experimental models. An in vivo synergism of the two agents, when administered to patients with metastatic prostate cancer refractory to hormone therapy, has been reported. To confirm these results, we administered this combination to a large number of patients with hormone-refractory prostate cancer (HRPC). Methods. Fifty-six patients with metastatic HRPC were treated with oral estramustine 140 mg three times a day and oral etoposide 50 mg/m2/day for 21 days. Therapy was discontinued for 7 days and the cycle was then repeated. Therapy was continued until evidence of disease progression or unacceptable toxicity occurred. To control for the possible interference of an antiandrogen withdrawal effect, all patients discontinued antiandrogen therapy and were not enrolled in the study unless there was evidence of disease progression. Results. Forty-five percent of 33 patients with measurable soft tissue disease demonstrated an objective response, which included five complete and ten partial responses. Among 52 patients with osseous disease, 17% showed improvement and 50% showed stability of bone scan. Thirty patients (58%) demonstrated a decrease of more than 50% in pretreatment prostate-specific antigen (PSA) levels. The median survival of all patients was 13 months. Good pretreatment performance status, measurable disease response, improvement or stability of bone scan, and PSA response were important predictors of longer survival. Conclusions. We conclude that the combination of estramustine and etoposide is an active and well-tolerated oral regimen in HRPC.

Approximately 20% of patients with multiple myeloma are recognized by chance without significant symptoms. In order to prevent morbidity with timely therapy, reliable criteria are needed that distinguish those likely to show early or late disease progression. Multiple clinical features were assessed in 101 consecutive, asymptomatic and previously untreated patients. Patients with one or more lytic bone lesions were excluded because this feature had been found previously to be associated with early progression. Multivariate analysis indicated that only serum myeloma globulin > 30 g/l. IgA protein type, and Bence Jones protein excretion > 50 mg/d remained as significant independent variables. The presence of two or more of these features signified high-risk disease with early progression (median 17 months) whereas the absence of any adverse variable was associated with prolonged stability (median 95 months) (P < 0.01). Magnetic resonance (MR) imaging of the spine was useful only in patients with one adverse feature and an intermediate time to progression (median 39 months). An abnormal pattern (40% of patients) helped to distinguish patients with an imminent complication from those with more stable disease. Because a serious complication (fracture, hypercalcaemia) occurred in 35% of patients with early disease progression, chemotherapy seems justified for selected patients with asymptomatic disease at diagnosis. The remaining patients were at such low risk for progression (median 6 years) that they may be followed safely at long intervals without treatment.

A phase II study of combination paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ)/gemcitabine was conducted in patients with non-small cell lung cancer (NSCLC) who had failed first, line docetaxel- or cisplatin- based chemotherapy. Eligibility criteria included histologically confirmed measurable stage IIIB or IV NSCLC and previous exposure to docetaxel, or cisplatin-based regimens. World Health Organization performance status between 0 and 2, adequate hematologic parameters, and adequate hepatic, renal, and cardiac function. Gemcitabine (900 mg/m2) was given on days 1 and 8 as a 30-minute infusion; paclitaxel (175 mg/m2) was administered on day 8 as a 3-hour infusion after appropriate premedication. Granulocyte colony- stimulating factor (150 μg/m2 subcutaneously) was given on days 9 to 15. Treatment was repeated every 3 weeks until patients experienced disease progression. From October 1995 to December 1996, 26 patients with advanced NSCLC were enrolled (three stage IIIB, 23 stage IV). All 26 patients were assessable for toxicity, and 24 were evaluable for response. Two complete (8%) and five partial (21%) responses were observed, for an overall response rate of 29% (95% confidence interval, 11% to 47%). The median duration of response was 2.5 months and the median survival was 8 months. A median of three courses per patient was administered, and the median interval between courses was 21 days. The median delivered dose was 579 mg/m2/wk gemcitabine and 54.5 mg/m2/wk paclitaxel, corresponding to a relative dose intensity of 0.97 and 0.96, respectively. Grade 314 neutropenia occurred in two patients (8%). Grade 3 conjunctivitis occurred in one (4%) patient and grade 213 neurotoxicity in eight (31%) patients. Grade 314 and grade 2 fatigue occurred in four (15%) and eight (31%) patients, respectively. Other toxicities were mild to moderate. These preliminary results suggest that the paclitaxel/gemcitabine combination is an active and well-tolerated salvage regimen in patients with NSCLC previously treated with docetaxel, or cisplatin-based chemotherapy. The paclitaxel/gemcitabine combination merits further evaluation as first-line treatment.

With current treatment modalities, most patients with early stage Hodgkin's disease (HD) can be cured. Patients destined to relapse, usually do so within 3 years after treatment completion. Late relapses do occur but disease recurrence beyond 15 years is extremely rare. We report a patient with clinical stage IIA nodular sclerosis HD, originally treated with radiotherapy alone, who relapsed 24 years after the initial diagnosis. Our patient's case indicates the possible need for lifelong surveillance of patients with Hodgkin's disease.

Anaplastic large cell lymphoma (ALCL) is a distinct clinicopathologic variant of intermediate grade non-Hodgkin's lymphomas (NHL) composed of large pleomorphic cells that usually express the CD30 antigen and interleukin (IL)- 2 receptors, and is characterized by frequent cutaneous and extranodal involvement. With variable frequency ALCL bear the t(2;5)(p23;q35) chromosomal translocation that fuses the nucleophosmin (NPM) gene on chromosome 5q35 to a novel protein kinase gene, Anaplastic Lymphoma Kinase (ALK), on chromosome 2p23. We determined the frequency of this translocation with e novel DNA polymerase chain reaction (PCR) technique using 0.5 μg of genomic DNA, 5'-primers derived from the NPM gene and 3'-primers derived from the ALK gene and hybridization with internal probes. The presence of amplifiable DNA in the samples was tested with the inclusion in the PCR reaction of oligonucleotide primers designed to amplify a 3016-bp fragment from the β-globin locus. NMP-ALK fusion amplicons were detected using DNA isolated either from all three ALCL cell lines tested, or from all four primary ALCL tumors known to contain the t(2;5)(p23;q35) translocation. Nested amplicons were detected by hybridization in 100% of specimens diluted 104-fold and in 20% of those diluted 105-fold. We subsequently examined archival genomic DNA from 20 patients with ALCL, 39 with diffuse large cell, 2 with mantle cell, 20 with peripheral T cell, 13 with low-grade NHL, 31 with Hodgkin's disease (HD), and 6 with lymphomatoid papulosis. Fusion of the NPM and ALK genes was detected in three of 18 patients with ALCL who had amplifiable DNA (17%, 95% confidence intervals 4% to 41%), but not in any patients with other NHL, HD, or lymphomatoid papulosis. The amplicon sizes were different in all cell lines and patients reflecting unique genomic DNA breakpoints. We conclude that with genomic DNA-PCR the rearrangement of the NPM and ALK loci is restricted to patients with ALCL. Further studies are needed to determine the prognostic significance of the NPM-ALK rearrangement, to determine whether its detection can aid in the differential diagnosis between ALCL, Hodgkin's disease, and lymphomatoid papulosis, and to establish the usefulness of the genomic DNA PCR in the monitoring of minimal residual disease in those patients whose tumors bear the t(2;5).

Objectives. For patients with prostate specific antigen (PSA) values of 4-10 ng/mL, some urologists perform prostatic biopsies depending upon the findings of digital rectal examination (DRE) and transrectal ultrasonography (TRUS), and others perform biopsies on most of these men regardless of the findings of DRE and TRUS. The purpose of this study was to examine whether the information given by the measurement of the ratio of free to total (F/T) PSA can alter decision-making on prostatic biopsy. Methods. One hundred and two (102) men with PSA values between 4 and 10 ng/mL, were included in this study. All men were examined with DRE and TRUS; a F/T PSA ratio was also measured, and six prostatic biopsies were taken from each patient. Results. In 102 men who were biopsied, 22 (21.5%) prostatic carcinomas were identified. Among these 22 cancer patients, 13 had abnormal findings in DRE and/or TRUS and would have been biopsied and diagnosed anyway. If we use only the F/T PSA ratio (cut-off value 0.20) to decide whom to biopsy, we would have diagnosed 16/22 cancers; the difference between these two procedures was not statistically significant (P = 0.17). If we decide to biopsy those patients who have abnormal findings in DRE and/or TRUS and those who have a F/T PSA ratio <0.20, we would diagnose 20/22 cancers (P = 0.05) and at the same time, reduce the unnecessary biopsies from 80 to 41 (48%). With a PSA value between 4 and 10 ng/mL and no findings in DRE and TRUS and at the same time with a F/T PSA ratio ≤0.20, we would have to perform biopsies in 20.5 men to find one cancer. On the other hand, in patients with suspicious findings in DRE and/or TRUS and a F/T PSA ratio <0.20, in every two men that we biopsy we would find one cancer. Conclusion. We believe that among patients with PSA values between 4 and 10 ng/mL after performing DRE and TRUS, the additional information of F/T PSA ratio can help since it increases the number of cancers detected and reduces the number of unnecessary biopsies.

Background. Skeletal complications are a major clinical manifestation of multiple myeloma. These complications are caused by soluble factors that stimulate osteoclasts to resorb bone. Bisphosphonates such as pamidronate inhibit osteoclastic activity and reduce bone resorption. Methods. Patients with stage III multiple myeloma and at least one lytic lesion received either placebo or pamidronate (90 mg) as a four-hour intravenous infusion given every four weeks for nine cycles in addition to antimyeloma therapy. The patients were stratified according to whether they were receiving first-line (stratum 1) or second-line (stratum 2) antimyeloma chemotherapy at entry into the study. Skeletal events (pathologic fracture, irradiation of or surgery on bone, and spinal cord compression), hypercalcemia (symptoms or a serum calcium concentration ≥12 mg per deciliter [3.0 mmol per liter]), bone pain, analgesic-drug use, performance status and quality of life were assessed monthly. Results. Among 392 treated patients, the efficacy of treatment could be evaluated in 196 who received pamidronate and 181 who received placebo. The proportion of patients who had any skeletal events was significantly lower in the pamidronate group (24 percent) than in the placebo group (41 percent, P<0.001), and the reduction was evident in both stratum 1 (P=0.04) and stratum 2 (P=0.004). The patients who received pamidronate had significant decreases in bone pain and no deterioration in performance status and quality of life. Pamidronate was well tolerated. Conclusions. Monthly infusions of pamidronate provide significant protection against skeletal complications and improve the quality of life of patients with stage III multiple myeloma.

More effective and safer regimens are needed for patients who have advanced multiple myeloma resistant to or relapsing despite prior treatment with alkylating agents and VAD. We treated 58 such patients using the combination of twice daily cyclophosphamide (total dose 1.8 g/m2) and VAD (hyperCVAD). Treatment was given to outpatients followed by G-CSF at 5 μg/kg/d until granulocyte recovery. Twenty-three patients responded (40%), with a median duration of granulocyte depression to less than 500/μl of 4 days and a mortality rate of 2%. The median survival time for all patients was 15 months, and the median remission time of responding patients was 8 months. Patients who had low LDH, low B2M, or primary resistant disease lived significantly longer than patients without these features. The combination of fractionated cyclophosphamide and VAD provided an effective and safe rescue treatment for many patients who had advanced myeloma resistant to standard therapies.

This is a brief presentation of the emerging molecular concept of prostate cancer as regards the diagnosis and staging of the disease, analysis of tumour response to hormone-depletion therapy, and the cellular mechanisms that underly progression of the organ-confined tumour toward systemic dissemination and inevitable lethal disease.

Purpose: We assessed the incidence, clinical and radiological features, and prognosis of patients with renal lymphoma. Materials and Methods: We studied 210 patients with symptoms, signs and radiological findings suggestive of renal cell carcinoma. Results: Final diagnosis in 6 of 210 patients (3%) was primary renal lymphoma. Radiological features were similar to those of renal cell carcinoma. Five of the 6 patients had an International Prognostic Index score of greater than 1. Despite appropriate chemotherapy, only 2 patients remain with complete remission. Conclusions: Primary renal lymphoma is unusual but not rare. The relatively poor prognosis in our patients could be attributed to the adverse prognostic factors associated with aggressive nodal lymphomas.

Fludarabine monophosphate (Fludara) is a purine analogue which entered clinical trials in 1982. Although inactive in solid tumors, Fludara has marked activity in indolent lymphoproliferative disorders. The exact mechanism of action of Fludara is uncertain. Fludara has been established as the most active single agent in chronic lymphocytic leukemia (CLL) in single arm and comparative clinical trials. The activity has been demonstrated in both previously treated and initially treated patients. Marked activity has been noted in patients with low grade lymphoma, in particular, those with a follicular morphology and in Waldenstrom's macroglobulinemia. Combinations of fludarabine with alkylating agents, anthracyclines, and anthraquinones have led to clinically useful combination approaches. The ability of fludarabine to modulate the levels of the triphosphate form of cytosine arabinoside (ara-C) in acute leukemia cells has led to the development of combinations of fludarabine and ara-C. These combinations have demonstrated marked activity in treatment of relapsed and previously untreated patients with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). The ability to modulate the activity of pyrimidines and to inhibit repair of DNA damage caused by alkylating agents, anthracyclines, and other DNA active drugs suggest that the future of fludarabine will be in combination approaches to modulate the activity of other agents. These activities may extend its role to use in solid tumors.

Forty-eight adult patients with recurrent or refractory intermediate grade or immunoblastic lymphoma received high-dose carmustine (BCNU), etoposide, Ara C and cyclophosphamide (BEAC), followed by autologous bone marrow transplantation (BMT). Median follow-up is 906 days (range 613-2067 days). The complete remission rate was 42% and 22% had a partial response. Actuarial failure-free survival is 30% ± 6.6%. Twenty one patients relapsed or progressed. Only one relapse occurred > 1 year after autologous BMT. Adverse prognostic factors for failure-free survival include high LDH at the time of autologous BMT, chemotherapy-refractory disease and multiple prior relapses. Patients with chemotherapy responsive first salvage (those achieving first CR only with salvage chemotherapy and those with first relapse, responding to salvage chemotherapy) had a failure-free survival of 52% ± 10% vs 12% ± 6% for those with more advanced disease. Of 13 patients who had no adverse factors, only two relapsed. Treatment-related mortality occurred in 23%, including infection (n = 4), cardiac toxicity (n = 4), pulmonary toxicity (n = 2) and hemorrhage (n = 1). Pulmonary toxicity was more common among patients who had received prior radiation-therapy to the chest. BEAC chemotherapy with autologous BMT is an effective but relatively toxic regimen for patients with relapsed or refractory lymphomas. The combination of chemotherapy-responsive disease after failure of one chemotherapy regimen and normal LDH identifies patients with a favorable prognosis. Alternative cytotoxic regimens require evaluation, with the goal of reducing treatment related mortality. More effective cytoreductive therapy is required for patient with poor prognostic features.

Since rising serum lactate dehydrogenase (LDH) heralds progression in patients with lymphoma or myeloma we investigated the significance of its elevations during chemotherapy supported by granulocyte (G-) or Granulocyte-Macrophage (GM-) colony stimulating factors (CSF). To exclude effects of resistant disease we analyzed 52 courses of therapy in 36 responding patients. During hematologic recovery LDH increased above normal in 53% and 85% of patients with leukocyte counts of 10,000/mUL and 15,000/kmUL, respectively. After CSF discontinuation LDH fell to or towards normal during 20 courses with adequate follow-up. Therefore rising serum LDH in patients with lymphoma or myeloma may be caused the CSF administration during chemotherapy and not by progressive disease. Proper identification of this effect can prevent unnecessary tests or treatment delays. © 1995 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted.

The clinical spectrum of MM is variable. Infiltration of bone and bone marrow by malignant plasma cells results in severe osteopenia, lytic lesions, pathological fractures and anaemia. Occasionally, significant numbers of plasma cells circulate in the bloodstream. Hypercalcaemia and Bence Jones proteinuria are the main reasons for renal impairment, but amyloidosis and monoclonal immunoglobulin deposition should also be considered. Neurological impairment is most often due to spinal cord pressure by an extradural plasma cell tumour. In some patients, symptoms and signs of peripheral neuropathy may be present. Amyloidosis complicates the course of a minority of patients with MM and further impairs the performance of affected patients. Circulating monoclonal protein may increase serum viscosity, impair the function of platelets and coagulation factors, and behave as a cryoglobulin. The levels of uninvolved immunoglobulins are usually decreased, rendering patients susceptible to various bacterial infections. One or more of these complications provides a clue for the diagnosis, forms the basis for defining prognosis and must be managed expeditiously and concurrently, with the institution of specific treatment for the myeloma. © 1995 Baillière Tindall. All rights reserved.

High-dose thioTEPA is used frequently in myeloablative regimens for marrow transplantation, but the need for dose adjustments in obese patients has not been explored. We determined the pharmacokinetics of thioTEPA and its metabolite TEPA during first-dose infusion of thioTEPA 150-250 mg/m2 given daily for 3 days in combination with busulfan and cyclophosphamide, and evaluated the results for correlations with toxicity and dosing strategies. The study included 15 adults undergoing marrow transplantation for hematologic malignancies. Plasma samples were obtained at various times over a 24-h period, and concentrations of thio TEPA and TEPA were measured by gas chromatography. At 22-24 h after initiation of a 4-h infusion, the mean ±SE plasma concentration of thioTEPA was 124±63 ng/ml, while that of TEPA was 235±69 ng/ml. For CFU-GM and BFU-E growth in vitro, the IC50s of thioTEPA were 83 ng/ml and 16 ng/ml, respectively, and the IC50s of TEPA were 141 ng/ml and 47 ng/ml, respectively. Using a twocompartment model, the mean thioTEPA Vc was 47.4±4.7 l/m2, t1/2α 19±5 min, t1/2β 3.7±0.5 h, and plasma clearance 302±21 ml/min per m2. The mean AUCs were 6.9-16.2 mg h/l for thioTEPA and 8.9-21.2 mg h/l for TEPA, while the mean peak concentrations were 0.95-2.08 μg/ml for thioTEPA and 0.88-1.90 μg/ml for TEPA. There was a significant association of grades 2-4 maximum regimen-related toxicity (RRT) with TEPA peak >1.75 μg/ml and with combined thioTEPA and TEPA AUC >30 mgh/l (5/6 vs 0/9, P=0.01 for both comparisons), suggesting that drug exposure was an important determinant of toxicity and, potentially, efficacy. ThioTEPA Vc correlated best with adjusted body weight (r=0.74, P=0.0015). In an evaluation of 74 adults receiving thioTEPA 750 mg/m2 in combination with busulfan and cyclophosphamide, the maximum RRT for patients at ideal weight was significantly greater than that for obese patients dosed on ideal weight (mean RRT grade 1.7 vs 1.0, P=0.004) but did not differ from the maximum RRT for obese adults dosed on actual or adjusted weights. We recommend that for obese patients thioTEPA be dosed on adjusted body weight. Measurements at time-points after 24 h are needed to determine when thioTEPA and TEPA concentrations are below myelosuppressive levels and safe for marrow infusion. © 1995 Springer-Verlag.

Myeloablative therapy supported by autologous bone marrow or blood stem cell transplantation was assessed in 41 patients who had multiple myeloma resistant to vincristine‐doxorubicin by continuous infusion with high‐dose dexamethasone (VAD) or other high‐dose dexamethasone regimens. In patients who had high or intermediate tumor mass, the myeloma cell mass was reduced by more than 75% in 56% of patients and the survival time quadrupled in comparison with that of a matched control group. Later treatment resulted in a lower response rate and shorter remission. Current myeloablative regimens supported by autologous stem cells provided a useful treatment for patients who had advanced primary resistant multiple myeloma. Such treatment should be given early in the disease course to provide the best chance for remission, collecting blood stem cells with facility, and preventing complications that would increase the risk of the procedure. Copyright © 1995 AlphaMed Press

In this Phase I clinical trial, six multiple myeloma patients who had not responded to conventional therapy and were scheduled for bone marrow transplantation received a bone-seeking radiopharmaceutical for bone marrow ablation. The pharmacokinetics, dosimetry, and toxicity of this radiopharmaceutical were studied. Methods: Patients received from 519 mCi to 2.1 Ci (19.2 GBq to 77.7 GBq) of holmium-166 (166Ho) complexed with a bone-seeking agent, DOTMP (1,4,7,10-tetraazacyclododecane-1,4,7,10- tetramethylene-phosphonic acid). The reproducibility of pharmacokinetics from multiple injections of 166Ho-DOTMP administered to these myeloma patients was demonstrated from blood (r2 = 0.926) and whole-body retention (r2 = 0.983), which allowed therapeutic parameters to be determined from a diagnostic study. Results: Over 50% of the 166Ho-DOTMP injected dose was excreted within 2-3 hr postinjection, increasing to 75%-85% over a 24-hr period. Rapid blood clearance minimized radiation dose to nontarget tissue: less than 10% of the injected activity was retained in the blood pool at 1 hr postinjection, and less than 2% remained after 5 hr. The total radiation absorbed dose delivered to the bone marrow for the six patients ranged from 7.9 Gy to 41.4 Gy. Conclusion: All patients demonstrated severe bone marrow toxicity with a white blood cell (WBC) count < 1,000 cells/μl, two patients exhibited marrow ablation (WBC count < 100 cells/μl), and no other toxicity ≥grade 2 was observed in any of the patients.

Primary lymphoma of the prostate was diagnosed in 3 patients corresponding to 0.1 percent of those with previously untreated lymphoma and 0.09 percent of those with previously untreated prostatic malignancy presenting to our cancer between January 1, 1980 and December 31, 1993. All 3 patients had prostatism at presentation that caused renal failure in 2. After treatment with doxorubicin-based combination chemotherapy appropriate for the stage and the specific histological subtype, all 3 patients achieved a complete remission and remained free of disease after a minimum followup of 3 years. Our results suggest that primary prostatic lymphoma is not necessarily associated with a poor outcome. Review of the literature suggests that the poor prognosis reported for prostatic lymphoma might be explained by treatment that was acceptable at the time but would be considered suboptimal by current criteria. We recommend through staging in all patients with prostatic lymphoma and treatment with a doxorubicin-based regimen according to disease stage and histological classification. © 1995 American Urological Association, Inc.

Purpose: To assess the prognostic significance of magnetic resonance (MR) imaging in patients with newly diagnosed asymptomatic multiple myeloma. Patients and Methods: Thirty-eight consecutive patients with asymptomatic myeloma of low tumor mass and negative skeletal surveys underwent MR imaging of the thoracic and lumbosacral spine. The presence and patterns of marrow involvement were correlated with standard laboratory parameters and time to disease progression. Results: Nineteen patients (50%) had evidence of marrow involvement at spinal MR imaging. MR patterns of marrow involvement were classified as diffuse (five patients), variegated (nine), and focal (five). Patients with abnormal MR imaging studies required therapy after a median of 16 months, versus 43 months for those with normal MR studies (P < .01). Conclusion: Abnormal marrow patterns were present in half of patients with asymptomatic myeloma. An abnormal MR study of the spine identified asymptomatic patients who were likely to require treatment earlier than those with a normal MR study. A normal MR pattern provided additional justification to defer institution of chemotherapy. However, MR imaging remains an investigational tool to stage patients with multiple myeloma until more data are accumulated.

Background: Few effective treatments are available for patients with Waldenstrom's macroglobulinemia that is resistant to standard therapies. We assessed the activity of 2-chlorodeoxyadenosine (2CdA) in patients with resistant macroglobulinemia in order to identify those most likely to benefit. Patients and methods: 2-chlorodeoxyadenosine was given to 46 consecutive patients with Waldenstrom's macroglobulinemia resistant to a combination of an alkylating agent and a glucocorticoid. Two courses were administered to outpatients at a dose of 0.1 mg/kg body weight per day for a 7-day continuous infusion using a portable pump through a central venous catheter. Responding patients were followed without further therapy. Results: Twenty of 46 patients responded to 2CdA therapy (43%; 95 CI; 29 to 60%) with a significantly higher frequency of benefit among patients with disease relapsing off therapy (78%) or with primary resistant disease within the first year (57%) than in those with later phases of disease (22%). The median survival after treatment was 28 months and the median progression-free survival of responding patients was 12 months. The longest survival was measured in patients with primary refractory disease (projected median 36 months) and the shortest in those with disease in refractory relapse (median 13 months). Conclusion: 2-Chlorodeoxyadenosine is active against macroglobulinemic lymphoma resistant to standard regimens and most effective in patients with disease relapsing off treatment or during the first year of primary refractory disease. Little benefit was observed among patients with later phases of resistant disease who should receive alternative treatments. © 1995 Kluwer Academic Publishers.

Few effective treatments are available for patients with multiple myeloma that is resistant to vincristine-doxorubicin by continuous infusion with high dose dexamethasone (V AD). In order to modulate p-glycoprotein, the multidrug resistance gene product, we administered a VAD-cyclosporine combination to patients with confirmed resistance to VAD. Twenty-five patients with multiple myeloma resistant to VAD received cyclosporine 4 mg/kg infused over 2 hours followed by a continuous infusion of 10 mg/kg/24 hrs for a total of 108 hours. VAD was given concurrently as a continuous infusion of vincristine 0.3 mg and doxorubicin 9 mg/m2 daily for 4 days with oral dexamethasone 20 mg/m2/day for 4 days beginning on days 1,9 and 17. Clinical response and toxicity were correlated with MDR expression in plasma cells and the effects of cyclosporine on liver function. Six of 25 patients responded (24%; 958 CI 9-45% with a median remission time of 7 months. Clinical response did not correlate with either the measured or the calculated MDR expression in plasma cells. Responses occurred more frequently in patients who developed high cyclosprine blood levels and paralytic ileus. The occasional benefit from VAD-cyclosporine for resistant multiple myeloma appeared to be due to a higher bioeffective dose of VAD rather than successful modulation of MDR. © 1995 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted.

Objective To assess whether it is worthwhile to screen asymptomatic men for prostate Cancer using serum prostate specific antigen (PSA) and to determine how many patients could be cured of prostatic carcinoma if detected by screening. Patients and methods Between June 1992 and January 1994 the serum PSA level of 1400 asymptomatic men over 50‐years‐old was assessed. Those men with PSA levels < 4 ng/mL were not evaluated further. Those men with PSA levels of 4–10 ng/mL underwent digital rectal examination (DRE) and transrectal ultrasonog‐raphy (TRUS) and biopsies were taken when there were significant findings on DRE and/or TRUS. If the PSA levels were > 10 ng/mL patients were submitted for DRE and TRUS and. even if both examinations were negative, random biopsies were taken. Where Cancer was detected the tumour was staged and if it was a clinically confined tumour a radical retropubic prostatectomy was performed. The pathological and clinical stages of the disease were then compared. Results The majority of patients (95%) had PSA levels of < 4 ng/mL. Forty‐nine men had PSA levels of 4–10 ng/mL and of these 28 were biopsied, which detected 12 (24.5%) carcinomas. There were 20 men with PSA levels > 10 ng/mL and among them 11 (55%) were found to have carcinomas. Combining these figures, among the 1400 men there were 69 cases with PSA levels >4 ng/mL and, using DRE and TRUS, 23 patients (33%) were diagnosed as having prostatic adenocarcinomas. Among these, one had metastatic disease, three had lymph node micrometast‐ases during surgical exploration and 19 underwent radical prostatectomies. The pathological and clinical stages agreed in only eight patients. Conclusion Only eight patients can be considered as cured because of the screening protocol and even this result is overoptimistic, as the future biological behaviour of these tumours is unknown. Therefore we cannot recommend screening for prostatic carcinoma among asymptomatic men in Greece. Copyright © 1995, Wiley Blackwell. All rights reserved

Manifestations of macroglobulinemic lymphoma include lymphadenopathy, splenomegaly and bone marrow involvement. Renal presentations are unusual and complications of renal function are even less frequent. A review of all patients diagnosed with Waldenström macroglobulinemia at our institution from January 1987 to December 1993, revealed 4 cases (6% with renal presentations. We describe these cases with their associated clinical and radiologic features. © 1995 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted.

After a sequence of standard and intensive therapies, approximately 70% of patients with multiple myeloma achieve a remission of good quality and of many months duration. Yet the disease remains incurable because the high residual burden of approximately 1010 tumor cells cannot be eradicated. Initial disease control, followed by long unmaintained or maintained remissions and by repeated recontrol of relapsing disease, provides the best chance for a long survival time of good quality. Since melphalan-prednisone became available, many other chemotherapy programs have been studied. For selected groups of patients, the most useful regimens are VAD, high-dose dexamethasone, high-dose alkylating agent therapy, and myeloablative therapy plus autologous cell transplantation. Other programs, such as treatments using combinations of alkylating agents in standard doses or interferon alfa, remain unproven despite prolonged study. Until the mortality rate associated with allogeneic bone marrow transplantation can be reduced substantially, the role of intensive treatment supported by this procedure will be limited. Current testing of agents such as paclitaxel, new agents that suppress MDR, topoisomerase I inhibitors, and myeloablative bone-seeking isotopes may lead to future improvements.

Purpose: To determine the significance of the International Prognostic Index (IPI) score in adults with testicular lymphoma treated with doxorubicin-based regimens. Patients and Methods: Untreated adults with testicular lymphoma who presented between 1969 and 1993 were studied. Those with Ann Arbor stages III and IV were included if they had a testicular mass at presentation. Results: We identified 22 patients, 21 with intermediate-grade and one with high-grade lymphoma. All 10 patients with an IPI score ≤ 1 had Ann Arbor stage I disease, whereas the 12 with an IPI score more than 1 had Ann Arbor stage II to IV disease. Complete remission (CR) was achieved in 73% of patients. At 153 months, 22% of all complete responders and 40% and 0% of those with IPI scores ≤ 1 and more than 1, respectively, remained in CR (P = .01). With a median follow-up time of 113 months for survivors, the failure-free survival (FFS) rate at 153 months was 16% for all patients or 32% and 0% for those with IPI scores ≤ 1 and more than 1, respectively (P = .02). The CNS or contralateral testis were involved in all patients who failed to respond to primary therapy and in 50% of those who relapsed from CR. Conclusion: The prognosis of patients with testicular lymphoma appears poor despite doxorubicin-based chemotherapy. On the basis of failures in the CNS and contralateral testis, we recommend prophylactic intrathecal chemotherapy and scrotal radiotherapy for all patients. Those with an IPI score ≤ 1 can be treated with conventional doxorubicin-based regimens, but those with an IPI score more than 1 should be considered for investigational systemic therapy. © 1995 by American Society of Clinical Oncology.

Between 1980 and 1988, 126 patients with leukemia were treated with piperazinedione and fractionated total body irradiation (TBI) followed by allogeneic bone marrow transplantation from HLA matched siblings. Sixty‐one patients had acute myelogenous leukemia, 46 acute lymphoblastic leukemia, and 19 chronic myelogenous leukemia. Patients with acute leukemia in first complete remission were transplanted only if perceived to have a low probability of remaining in remission with conventional therapy. The toxicity from the preparative regimen was similar to that of cyclophosphamide and TBI except that none of the patients in the study had hemorrhagic cystitis or veno‐occlusive disease. After a median follow up of 114 months, 29 patients (23%) are still alive without relapse. The survival of patients with acute myelogenous or lymphoblastic leukemia transplanted in their first remission were 35% and 43%, respectively. The survival of patients transplanted in their first chronic phase of chronic myelogenous leukemia was 60%. The results of this preparative regimen are comparable to those of cyclophosphamide and TBI. © 1994 Wiley‐Liss, Inc. Copyright © 1994 Wiley‐Liss, Inc., A Wiley Company

The major clinical experience with fludarabine has been obtained in patients with chronic lymphocytic leukemia (CLL). In the initial studies in previously treated patients with CLL, the complete and partial response rate (CR + PR) was over 50% and in previously untreated patients with CLL, a CR + PR rate of 75-80% was noted with or without the addition of prednisone. Subsequent clinical trials have also demonstrated major activity with fludarabine in Waldenstrom's macroglobulinemia. Fludarabine was noted to be an active agent in indolent lymphoma in phase I/II studies. Approximately 60% of patients with follicular lymphoma respond to fludarabine when it is administered as a single agent. Many of these remissions are complete remissions despite patients having received extensive prior therapy. Combination programs are being developed for application in CLL and indolent lymphoma. Because of the activity of fludarabine in inhibiting DNA repair, it has been combined with cisplatinum and cytosine arabinoside and plans are in place to explore the radiation sensitizing effect of fludarabine in clinical trials. A combination of fludarabine plus ara-C is now being used in patients with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) and a combination of fludarabine, ara-C, and G-CSF (FLAG) has been combined with idarubicin for the management of these conditions. Many of these activities of fludarabine are associated with its interaction with many enzymes which are important in DNA and RNA metabolism and in DNA repair. It is anticipated that these actions will be explored in a wider range of studies subsequently. © 1994 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted.

Fludarabine is the most active single agent that has been studied in CLL. The response rate for both previously untreated and previously treated patients is higher than combinations that have been studied. Myelosuppression is dose-limiting with substantial evidence of suppression of normal T- lymphocytes, both in patients receiving fludarabine as a single agent and in patients being treated with fludarabine plus prednisone. Along with the myelosuppression noted in advanced stage disease, infections are the most common complication with many of the infections being associated with T-cell immunodeficiency rather than the more traditional characteristics of neutropenia and hypogammaglobulinemia. Comparative clinical trials are being conducted in Europe with a cyclophosphamide, doxorubicin, prednisone regimen in previously untreated and previously treated patients. In the United States, previously untreated patients are being entered in a trial comparing fludarabine with chlorambucil alone or the combination of fludarabine and chlorambucil. The eventual contribution of fludarabine to the management of chronic lymphocytic leukemia awaits the conclusion of these clinical trials.

We investigated the antitumor activity and toxicity of cisplatin and interferon-α2B as the primary treatment of penile carcinoma. A total of 13 consecutive patients with nonmetastatic, histologically confirmed invasive squamous cell carcinoma of the penis underwent treatment consisting of 20 mg./m.2 cisplatin intravenously and 5 x 106 μ./m.2 interferon-α2B subcutaneously daily for 5 consecutive days. An equivalent dose of interferon was then administered subcutaneously every 2 days for 3 weeks and the regimen was repeated at 28-day intervals. Of 12 evaluable patients 9 responded: 4 achieved a pathologically confirmed complete remission of 38+, 21+, 10 and 7 months in duration (2 with relapse were treated with local therapy and remain with no evidence of disease), and 5 achieved a partial response, underwent surgical removal of residual disease and remained disease-free for 14+ to 24+ months. The most significant toxicities were anemia in 5 patients and reversible renal impairment in 3 but no patient had neutropenic fever or required platelet transfusion. We conclude that primary treatment with cisplatin and interferon-α2B induced responses in 75% of 12 patients with penile carcinoma and allowed for a less radical operation than originally scheduled. A larger number of patients and longer followup will be required to confirm these encouraging preliminary results.

Background: Fludarabine monophosphate and 2Chlorodeoxyadenosine are nucleoside analogues with activity against Waldenström macroglobulinemia. However, it is not clear whether prior exposure to one analogue precludes response to the other compound. Patients and methods: Fourteen patients with Waldenström's macroglobulinemia and prior exposure to fludarabine were treated with two courses of 2chlorodeoxyadenosine. Results: Three out of four patients that had previously responded to fludarabine and were relapsing from unmaintained remission, achieved a partial response with 2chlorodeoxyadenosine therapy. However, only one out of 10 patients with disease resistant to fludarabine responded to 2chlorodeoxyadenosine. Conclusions: 2chlorodeoxyadenosine may be effective in patients with Waldenström macroglobulinemia sensitive to fludarabine. However, this compound has limited activity for patients with disease resistant to fludarabine. © 1994 Kluwer Academic Publishers.

This study assessed the feasibility and effect of blood progenitors as the only source of haemopoietic support for myeloablative therapy for patients with primary resistant multiple myeloma and markedly infiltrated bone marrow. 17 patients with advanced, primary resistant myeloma received a priming regimen of cyclophosphamide (3 g/m2) and etoposide (900 mg/m2) with GM-CSF. During haematological recovery, at least 2 x 106 CD34+ mononuclear cells/ kg were collected from each patient with 4-12 leukaphereses. High-dose chemotherapy was then given which consisted of thiotepa (750 mg/m2), busulfan (10 mg/kg) and cyclophosphamide (120 mg/kg) followed by reinfusion of the blood progenitors. Haemopoietic reconstitution was rapid with recovery of granulocytes to >1.0 x 109/l after a median of 10 d and of platelets to 50 x 109/l after a median of 29 d. The myeloma responded in 10/17 patients for a projected median duration of at least 12 months. Survival was prolonged significantly in comparison with the outcome of control patients who did not receive intensive treatment. Blood progenitors, assessed from the number of CD34+ cells, produced early haemopoietic recovery after myeloablative therapy that induced sustained control of advanced and resistant multiple myeloma.

Few effective regimens are available for patients with advanced multiple myeloma resistant to alkylating agents and VAD. We treated 65 patients with advanced and refractory multiple myeloma with the combination of cyclophosphamide (3.0 gm/m2) and etoposide (900 mg/m2) followed by GM-CSF at a daily dose of 0.125 mg/m. Thirty-five percent of patients responded with a 6% mortality rate. After a median of 2 months, 16 patients received myeloablative treatment supported by autologous bone marrow or blood stem cells. Four of ten previously resistant patients responded so that the overall response rate was 42% The median survival for all patients was 10 months and the median remission was 8 months. The median survival for patients with both low serum lactate dehydrogenase and B2 microglobulin, or for those who received myeloablative treatment, was projected at 18 months. Our combination of cyclophosphamide and etoposide provided an effective rescue treatment for many patients with advanced multiple myeloma resistant to conventional therapies. This program allowed early blood stem cell collection in support of subsequent myeloablative therapy for selected patients. © 1994 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted.

The utility of myeloablative therapy supported by autologous bone marrow (BM) or blood progenitor cells was assessed in 49 patients with multiple myeloma who had received at least 1 year of prior chemotherapy. Outcomes were compared with those of similar patients who did not receive intensive treatment primarily for socioeconomic reasons. Among patients with disease in resistant relapse despite treatment with vincristine-doxorobucin by continuous infusion with pulse dexamethasone (VAD), a 61% response rate was associated with a median remission time of 5 months. After primary resistance for more than 1 year, 6 of 15 patients responded and the overall survival was similar to that of control patients. For patients with melphalan-resistant disease that responded to VAD, the remission time was similar to that of control patients. Current myeloablative treatments supported by autologous BM or blood stem cells were useful to very few patients with multiple myeloma after the first year of chemotherapy.

Cis-platinum-based chemotherapy combinations have improved the outcome of patients with metastatic urothelial tumors, since two-thirds of these patients respond to treatment. Nevertheless, the majority of such patients have relapse within a median of 12 months. To define the pattern of failure and subsequent outcome, we retrospectively assessed 58 consecutive patients with relapse after prior response to cis-platinum-based combination chemotherapy. Of the patients who presented initially with local-regional metastases, 74% had relapse with involvement of a similar site, while only 26% of these patients had visceral metastases at relapse. The median survival after relapse was 9 months, and parameters associated with longer survival were local-regional relapse (10.7 months) and response to salvage chemotherapy (12.6 months). These data suggest that select patients with urothelial tumors and local-regional metastases may benefit from consolidation therapy with surgery or radiotherapy after maximum response to chemotherapy.

Among 750 previously untreated patients with multiple myeloma, 27 (4%) presented with plasma cell leukaemia. All but one patient had high tumour mass and, when compared with comparable patients without leukaemia, more frequent extraosseous involvement, thrombocytopenia, high serum lactate dehydrogenase and hypodiploid plasma cells. Most patients also had complex cytogenetic abnormalities. Treatment with standard melphalan-prednisone was ineffective, with a median survival of 2 months, but more intensive chemotherapy induced responses in approxirnately one-half of the patients, with a median survival of 20 months. Primary plasma cell leukaemia usually results from the proliferation and extramedullary expansion of immature plasma cells and requires prompt and intensive chemotherapy.

Regression of low-grade B cell gastric lymphoma of mucosa-associated lymphoid tissue after eradication of Helicobacter pylori with antibiotic therapy was recently shown in a small number of patients with low-volume tumors. A patient with a > 10 cm nodular gastric mucosa-associated lymphoid tissue lymphoma that caused hematemesis and weight loss is described. Antibiotic therapy of H. pylori resulted in full clinical recovery and resolution of the mass lesion and morphological features of lymphoma on routine histological examination. However, monotypic immunostaining of plasma cells persisted in a separate and grossly normal-appearing region of the stomach. Antibiotic therapy may be of benefit in patients with mucosa-associated lymphoid tissue lymphoma with mass lesions and significant signs and symptoms, but periodic search for residual lymphoma is needed. © 1994.

One hundred twenty-seven adults with advanced hematologic malignancies received thiotepa 450-750 mg/m2, busulfan 10 or 12 mg/kg, and cyclophosphamide 120 or 150 mg/kg as a preparative regimen for autologous (86 patients) or allogeneic (41 patients) marrow transplantation. Early regimen-related toxicity (RRT) was scored according to the Seattle toxicity grading system. Grade 1-4 RRT occurred in 94% of the patients. Grade 3-4 RRT was noted in 19 patients (9% of the autologous and 27% of the allogeneic marrow recipients) and included 6% hepatic, 5% pulmonary, 3% renal, 2% mucosal, 2% bladder, 2% cardiac, and 1% CNS toxicity at the grade 3 or 4 level. No patient experienced life-threatening or fatal gastrointestinal or cutaneous toxicity. A stepwise logistic regression analysis suggested that the higher busulfan dose, Zubrod performance status of 2 or 3, and ten or more previous cycles of chemotherapy were factors predictive of grade 3-4 RRT. The regimen-related mortality for all patients was 8% (95% Cl 4-14%). The incidence and spectrum of RRT for this novel drug combination are similar to those reported for the standard preparative regimens. Heavily pretreated patients with poor performance status receiving the higher busulfan dose have a higher incidence of severe or fatal RRT. © 1994 Springer-Verlag.

Objective: To determine the following: a reference range for serum calcitriol during hypercalcemia in a control group of patients with myeloma in whom calcitriol production is known to be appropriately suppressed; the incidence of elevated serum calcitriol levels in hypercalcemic patients with non-Hodgkin lymphoma according to this derived reference range; and the incidence of abnormal calcium metabolism in normocalcemia patients with non-Hodgkin lymphoma. Design: Prospective clinical study. Setting: Referral cancer center. Patients: 2 groups of hypercalcemic patients: 16 control patients with myeloma and 22 patients with non-Hodgkin lymphoma divided into those with elevated or normal serum calcitriol levels; 1 group of 22 normocalcemia patients with non-Hodgkin lymphoma. Measurements: Serum chemistries and intact parathyroid hormone, calcitriol, parathyroid hormone-related protein, and urinary electrolyte levels. Results: On the basis of the mean serum calcitriol level of the control group plus 3 standard deviations, the reference range for serum calcitriol during hypercalcemia was defined as less than 42 pg/mL. Although serum calcium and parathyroid hormone levels in the study patients were similar to those in controls, 12 of the 22 hypercalcemic patients with non-Hodgkin lymphoma (55%) had serum calcitriol levels greater than 42 pg/mL (range, 51 to 170 pg/mL). No features distinguished the patients with elevated serum calcitriol levels from those with normal levels. Seventy-one percent of normocalcemia patients with non-Hodgkin lymphoma were hypercalciuric, and 18% had serum calcitriol levels greater than the normocalcemic reference range (20 to 76 pg/mL). Conclusions: Serum calcitriol levels are elevated in most hypercalcemic patients with non-Hodgkin lymphoma in the absence of elevated serum levels of parathyroid hormone, which implicates extrarenal calcitriol production in the pathogenesis of this syndrome. Abnormal calcium metabolism, hypercalciuria, and dysregulated calcitriol production are also common in normocalcemic patients with non-Hodgkin lymphoma.

The value of early myeloablative therapy supported by autologous bone marrow or blood progenitor cells was assessed in 72 patients with multiple myeloma who were treated within 1 year of initial therapy. Forty-five patients were consolidated during remission, and 27 patients were treated for primary refractory disease. Outcomes were compared with those of similar patients who did not receive intensive treatment primarily for socioeconomic reasons. Among patients who had responded previously, myeloablative therapy increased the rate of complete remission from 5% to 45% (P < .01) but did not prolong progression-free intervals or survival times. The same treatment controlled the myeloma in 70% of patients with primary resistant disease and prolonged the median survival from 37 to 83 months (P = .03). Intensive treatment for primary resistant myeloma administered later in the disease course resulted in significantly lower response rates and shorter progression-free intervals. Current myeloablative regimens supported by autologous stem cells appeared useful primarily in patients with primary resistant disease during the first year of therapy.

Purpose: To determine the efficacy and toxicity of etoposide, cyclophosphamide, and fractionated total-body irradiation (TBI) as the conditioning regimen for allogeneic bone marrow transplantation (BMT) in patients with hematologic malignancies. Patients and Methods: Seventy-nine patients underwent BMT from a human leukocyte antigen (HLA)-identical sibling using cyclosporine/methotrexate for graft-versus-host disease (GVHD) prophylaxis. Thirty-four patients had early leukemia (acute leukemia or lymphoblastic lymphoma in first remission, chronic myelogenous leukemia [CML], or refractory anemia [RA]), and 45 patients had more advanced disease. Patients received etoposide 1,500 mg/m2 on day -8, followed by cyclophosphamide 60 mg/kg/d on days -7 and -6, and 10.2 Gy of TBI administered in six fractions of 1.7 Gy given twice daily for 3 days from day -3 to -1. Donor bone marrow was harvested and infused on day 0. Results: Patients with early leukemia had a disease-free survival rate of 53% ± 9% and an overall survival rate of 57% ± 10% at 3 years. Patients with advanced disease had a disease-free survival rate of 15% ± 5% and overall survival rate of 17% ± 5%. The actuarial relapse rate for the early-leukemia group is 33% ± 9% versus 69% ± 9% for patients with more advanced disease. Severe toxicity was most frequently manifested as pulmonary hemorrhage followed by multiorgan failure and death. The 100-day mortality rate for the early- leukemia group was 10% versus 50% for patients with more advanced disease. Conclusion: The combination of cyclophosphamide, etoposide, and TBI is a relatively safe and effective preparative regimen for patients with early hematologic malignancies. Controlled trials are needed to evaluate critically this combination versus other standard preparative regimens. Greater toxicity was observed in patients with advanced disease, and this program does not appear to offer any advantage over other regimens.

PURPOSE: To assess changes in the magnetic resonance (MR) appearance of the spine in patients with multiple myeloma who responded to chemotherapy. MATERIALS AND METHODS: Twenty patients with multiple myeloma underwent MR imaging of the spine before and after chemotherapy. Sagittal T1-weighted images were obtained before and after administration of contrast material. MR patterns of marrow involvement before treatment were classified as focal, diffuse, or variegated. The changes seen on MR images after treatment were analyzed and correlated with the clinical response as defined with standard criteria. RESULTS: Patterns of complete response included resolution of marrow abnormality or persistent abnormality without enhancement or with peripheral rim enhancement. Conversion of a diffuse to a variegated or focal pattern and a decrease in the amount of marrow abnormality with persistent enhancement were observed in patients who showed a partial response. Ten patients sustained new or progressive compression fractures after successful therapy. CONCLUSION: Recognition of spinal MR patterns of response to treatment supported the occurrence of remission in patients with multiple myeloma. MR findings may help clarify response to therapy in patients with equivocal clinical changes or nonsecretory myeloma.

Background: The treatment of multiple myeloma remains unsatisfactory and new active agents are needed. Paclitaxel is effective against a variety of solid tumors and we assessed the utility against multiple myeloma. Patients and methods: From March 1993 to May 1994, we treated 33 patients with newly diagnosed multiple myeloma with paclitaxel given intravenously at a dose of 125 mg/m2 over 24 hours (13 patients) or at a dose of 135 mg/m2 over 3 hours (20 patients). Results: Five of 33 patients responded (15%; 95% CI: 5 to 32%) with an unmaintained remission of 3-11+ months. Severe but reversible neutropenia was the major dose limiting toxicity, but myalgias and alopecia were also common. Conclusions: Paclitaxel was slightly active against multiple myeloma. Whether higher doses or new analogues of this agent can produce superior results requires further study. © 1994 Kluwer Academic Publishers.

Purpose: To assess the activity of 2-chlorodeoxyadenosine (2CdA) as primary therapy for patients with Waldenström's macroglobulinemia. Patients and Methods: 2CdA was given to 26 consecutive, previously untreated and symptomatic patients with Waldenström's macroglobulinemia. Two courses were administered to outpatients at a dose of 0.1 mg/ kg body weight per day for a 7-day continuous infusion using a portable pump through a central venous catheter. Responding patients were followed up without further therapy and were scheduled to receive two additional treatments with 2CdA on disease relapse. Results: Twenty-two of 26 patients responded to the 2CdA therapy (85%; 95% confidence interval [Cl], 65% to 96%), including three patients who achieved a complete response and 19 patients who had a partial response. Treatment was well tolerated, with no acute hematologic toxicity. A marked and sustained reduction of CD4+ lymphocytes occurred in all patients and may have contributed to a fatal infection with disseminated herpes simplex in one patient. With a median follow-up of 13 months, five patients have relapsed and all re-treated patients have responded again to 2CdA. Conclusion: 2CdA is highly active in previously untreated patients with Waldenström's macroglobulinemia. A limited program of treatment induced responses of good quality and long duration in more than 80% of patients. © 1994 by American Society of Clinical Oncology.

Summary— Collecting duct carcinoma (CDC) is a recently recognised histological variety of renal carcinoma (RC) considered to arise from the epithelium of the collecting ducts. Diagnosis of this entity depends on well defined gross and microscopic criteria and is supported by a characteristic immunostaining pattern. The clinical features of these patients, the natural course of the disease and its response to treatment have not been clearly established. Between 1980 and 1990 we treated 12 patients (median age 43 years, range 16–62) with collecting duct carcinoma of the kidney. In addition to being relatively young, each patient had a strong family history of associated malignancies. Survival was short (median 22 months) and 11 patients presented with locally advanced or metastatic disease. © 1993 British Journal of Urology

Background. Alpha‐interferon and dexamethasone are each effective in patients with multiple myeloma and have a combined inhibitory effect on the in vitro growth of myeloma colonies. The effect of combined therapy in newly diagnosed patients is unknown. Methods. Fifty‐one consecutive patients with previously untreated multiple myeloma of low tumor mass received primary therapy with 3 million units (mu)/m2/day of interferon administered subcutaneously for 20 days and 20 mg/m2 of dexamethasone given orally each morning for 4 days beginning on days 1, 9, and 17. Courses were repeated after a rest period of 14 days. Results were compared with those of similar patients who received primary treatment with dexamethasone alone in the same dose regimen. Results. The response rate was similar: 57% for patients treated with interferon‐dexamethasone and 48% for those treated with dexamethasone alone. Remission and survival times of both groups were identical. Twenty‐nine percent of patients resistant to interferon‐dexamethasone and 19% of patients resistant to dexamethasone responded subsequently to either standard melphalan‐prednisone or to a cyclophosphamide‐vincristine‐doxorubicin‐dexamethasone combination. These regimens were also effective in one third of patients with disease relapse despite interferon. Conclusion. In this nonrandomized study of previously untreated patients with multiple myeloma, the addition of interferon in a dose of 3 mu/m2/day to dexamethasone achieved results similar to those with dexamethasone alone. Copyright © 1993 American Cancer Society

Few effective regimens are available for patients with advanced multiple myeloma resistant to or relapsing after both alkylating agents and VAD. We treated 52 patients with advanced and refractory multiple myeloma with the combination of cyclophosphamide (3.0 g/m2) and etoposide (900 mg/m2) followed by GM‐CSF at a daily dose of 0.125 mg/m2 until recovery of granulocytes. 42% of patients responded with a median time of 19 d for recovery of granulocytes to 0.5 x 109/1 and a 4% mortality rate. Eight responding patients received a second myeloablative treatment supported by either autologous bone marrow (six patients) or blood stem cells (two patients). The median survival time for all patients was 11 months and the median remission time for responding patients was 8 months. The combination of cyclophosphamide and etoposide provided an effective rescue treatment for many patients with advanced multiple myeloma resistant to conventional therapies. This programme also allowed early marrow or blood stem cell collection in support of subsequent myeloablative therapy for selected patients. Copyright © 1993, Wiley Blackwell. All rights reserved

Multiple myeloma is a disseminated malignant neoplasm usually derived from a single clone of plasma cells. Patients with myeloma have diverse signs such as anemia, hypercalcemia, uremia, pathologic fractures, and recurrent infections. Extraosseous manifestations are found in less than 5% of patients with multiple myeloma. They can arise in any tissue, and their presence has been associated with more aggressive disease. The purpose of this assay is to illustrate the imaging findings of extraosseous myeloma and heighten awareness of this unusual manifestation of multiple myeloma.

purpose: To assess the response rate, remission duration, and survival of patients with Waldenström's macroglobulinemia treated with the adenine nucleoside analogue fludarabine. patients and methods: Twenty-eight patients with Waldenström's macroglobulinernia, of whom only 2 were previously untreated, received fludarabine at a dose of 20 to 30 mg/m2 intravenously daily for 5 days (20 patients) or 30 mg/m2 intravenously daily for 3 days (8 patients). Treatment was continued until maximum response was achieved. Responding patients were followed with no further treatment until relapse. results: Ten patients responded (36%), including the 2 previously untreated patients and 8 of 26 patients (31%) who were resistant to prior therapies. Uninaintained remissions lasted for a median of 38 months. There were no fatalities associated with this treatment. Previously untreated patients and those with a primary resistant disease of relatively short duration were more likely to benefit from this treatment. conclusion: Fludarabine is an effective salvage agent for the treatment of patients with resistant Waldenström's macroglobulinemia. Further investigations of fludarabine in untreated patients and in combination with other active agents are warranted. © 1993.

Fludarabine monophosphate (fludarabine) was initially discovered to have significant activity in indolent lymphoma and chronic lymphocytic leukemia (CLL). The major clinical experience with fludarabine is in previously treated patients with CLL. In such patients the complete and partial response rate (CR + PR) is over 50%. These results were obtained with 5-day schedules of fludarabine 25 to 30 mg/m2/d. Subsequent schedules have explored once-a- week fludarabine and a 3-day schedule every 4 weeks. These strategies, in particular the once-a-week schedule, have obtained inferior results. The addition of prednisone has not been associated with an improvement in response rate or survival. The application of fludarabine to previously untreated patients demonstrated a CR + PR rate of 75% to 80%. The addition of prednisone did not improve the response rate or survival in this group of patients. A significant concern in patients with CLL treated with fludarabine is a decrease in the CD4 and CD8 counts. Despite median posttreatment counts of approximately 200 CD4 lymphocytes/μL, the incidence of infections in patients in remission off therapy is low. Major clinical activity has been demonstrated with fludarabine in Waldenstrom's macroglobulinemia, in which more than one third of refractory patients achieve a CR or PR. Responding patients with anemia or thrombocytopenia have a marked improvement in blood counts. The duration of response has been long (>30 months) in most responders. The early activity of fludarabine as a single agent in phase I/II studies in indolent lymphoma subsequently has been confirmed by a number of investigators. Fifty percent to 60% of patients with follicular lymphomas respond to fludarabine as a single agent. A number of these responses are complete despite the patients having received extensive prior treatment. A number of combination programs are being developed in CLL and indolent lymphoma. The combination of fludarabine with doxorubicin and prednisone has been developed and is being studied in phase I/II clinical trials. In addition, combinations of fludarabine and cytarabine with or without cisplatin based on elegant preclinical pharmacokinetic rationales have been applied to CLL with impressive cytoreductive activity but significant myelosuppression. A new combination of fludarabine, mitoxantrone, and dexamethasone has been developed for use in lymphoma. Phase I studies demonstrated a high response rate, especially in follicular lymphomas, with a number of patients achieving complete remission. Subsequent phase II studies demonstrate a response rate of 89% in patients with indolent lymphoma. The enhancement of the formation of the triphosphate form of cytarabine in acute myelogenous leukemia blast cells has led to the study of fludarabine and cytarabine in previously treated patients with acute leukemia. The promising results in these patients have led to the application of the fludarabine and cytarabine combination in frontline patients with poor-risk disease and, subsequently, in those with better-risk disease. Results equivalent or superior to traditional combinations have been obtained. The same regimen has been applied to myelodysplastic syndrome patients with a response rate of over 50%. The addition of granulocyte colony-stimulating factor to fludarabine and cytarabine to enhance the cytotoxicity of cytarabine on acute myelogenous leukemia and myelodysplastic syndrome has further improved the response rate. These drugs have now been combined with Idarubicin (Adria Laboratories, Columbus, OH). Fludarabine has been demonstrated to have a marked impact on the inhibition of repair of DNA damage subsequent to radiation and exposure to cytotoxic substances such as cisplatin. These biologic effects have been used to develop clinical protocols exploring the combinations of fludarabine/cisplatin with or without cytarabine and fludarabine/radiation therapy. The expanding use of fludarabine in hematologic malignancies is related to its wide range of biochemical actions. Further use in combinations is anticipated.

Purpose: In recent years, increasing numbers of patients with asymptomatic multiple myeloma have been diagnosed by chance and followed without any therapy. Those at risk for early or late disease progression should be distinguished in order to prevent complications. This study defined prognostic factors that would predict the need for early treatment. Patients and Methods: We followed 95 patients with asymptomatic multiple myeloma without chemotherapy between 1974 and 1991. Magnetic resonance imaging (MRI) of the spine was conducted in 23% of patients with normal radiographs. An increase in serum myeloma protein to more than 50 g/L or new lytic bone lesions justified the institution of chemotherapy. Response to treatment and survival were assessed, and prognostic factors were defined for early or late disease progression by standard techniques. Results: The median time to progression in all patients was 26 months. The 25 patients with either a lytic bone lesion, or both serum peak greater than 30 g/L and Bence Jones proteinuria, had the shortest median time to progression of 10 months; the 27 patients without any harmful factor remained stable for a median of 61 months. MRI confirmed bone or marrow disease in half of the patients with normal radiographs and may assist in the prognostic staging. Despite the markedly different times of disease stability, the response rates and survival after chemotherapy were similar for all groups of patients. Conclusion: Among asymptomatic patients with multiple myeloma, the extent of disease at diagnosis and the subsequent rate of disease evolution were major factors in the total survival time. These patients are a markedly heterogeneous group who may benefit from different approaches to treatment according to defined risk factors. © 1993.

Sixty-eight patients with Waldenstrom's macroglobulinemia were treated either with fludar-abine (28 patients) or 2-chlorodeoxyadenosine (40 patients) and responding patients were followed without further treatment. Both programs were well tolerated and myelosuppression was moderate but reversible. Overall, 35 patients responded including 93% of previously untreated patients, 83% of those relapsing off therapy, 48% of patients with primary refractory disease and 15% of those treated during refractory relapse. With a median follow up of 18 months, only two of 15 previously untreated patients have relapsed whereas the median remission duration and survival of previously treated patients were 38 and 43 months respectively. Fludarabine and 2-chlorodeoxyadenosine are both highly active agents against Waldenstrom's macroglobulinemia, especially when administered early in the disease course. © 1993 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted.

Purpose: To assess prospectively the role of magnetic resonance (MR) imaging in the staging of patients with a solitary bone plasmacytoma (SBP). Patients and Methods: Twelve consecutive patients with an apparent SBP underwent MR imaging of both the primary tumor and the thoracic and lumbosacral spine to seek additional foci of marrow involvement that might have been undetected by standard skeletal survey. All patients received megavoltage irradiation (total dose, 40 Gy) to the primary lesion. Results: MR imaging of the thoracic and lumbosacral spine showed additional foci of marrow replacement in four of 1 2 patients, with signal characteristics identical to those of the primary tumor. In all four patients, the abnormal protein persisted at greater than 50% of the pretreatment value following radiation treatment. In contrast, the myeloma protein disappeared or was reduced by greater than 50% in five of the six patients with secretory disease and without additional marrow abnormalities. One of four patients progressed to multiple myeloma 10 months after diagnosis with new lesions on conventional radiographs in the same areas as detected previously by MR imaging. Conclusion; Four of 12 patients considered to have a SBP by standard criteria may have been understaged, because MR imaging showed additional marrow abnormalities consistent with myeloma. MR imaging of the spine may contribute to the initial staging of SBP, especially since some patients may be cured with radiotherapy. © 1993 by American Society of Clinical Oncology.

Purpose: To evaluate the role of serum β2-microglobulin (β2M) in the prognosis of patients with Hodgkin's disease. Patients and Methods: One hundred sixty previously untreated patients with Hodgkin's disease had serum β2M levels determined before initiation of treatment. Serum β2M was tested for its correlation with known prognostic factors for patients with Hodgkin's disease. These variables, including β2M, were correlated with complete remission (CR) rate and time to treatment failure (TTF). Univariate and multivariate analyses were performed. Results: Serum β2M levels greater than 2.5 mg/L were found in 29% of patients. Such elevation was more common in patients with more advanced-stage disease. Elevated serum β2M was an independent and powerful factor in the prediction of lower response rate and shorter TTF. Its impact appeared to be more significant in patients with advanced disease. Conclusion: Serum β2M appears to correlate with tumor stage in patients with Hodgkin's disease and elevated serum levels of this polypeptide predict a less favorable prognosis.

Forty patients with multiple myeloma received thiotepa (750 mg/m2), busulfan (10 mg/kg), and cyclophosphamide (120 mg/kg) (TBC) followed by autologous bone marrow or blood stem cell support. Granulocyte-Colony stimulating factor (G-CSF) was administered to accelerate hematopoietic recovery. Sixty-five percent of all patients responded to this treatment. Eighty-eight percent of patients transplanted in partial remission had a further reduction of the myeloma and 53% achieved a complete remission. Forty-eight percent of patients with refractory myeloma responded. All responding patients transplanted during partial remission or with primary refractory myeloma remain free of progression for a period of 4 to 24 months posttransplant, but the remission duration of patients treated in refractory relapse was short (4 months). Five of 24 patients transplanted with marrow and none of 16 receiving blood stem cells died of treatment-related complications. Use of blood stem cells resulted in more rapid granulocyte and platelet recovery. We conclude that TBC is an effective, relatively well tolerated, preparative regimen for patients with multiple myeloma. © 1993 by The American Society of Hematology.

Objective: To evaluate the activity of 2-chlorodeoxyadenosine (2CdA) in the treatment of patients with Waldenstrom macroglobulinemia. ■ Design: Uncontrolled phase II trial. ■ Setting: Tertiary, referral cancer center. ■ Patients: Twenty-nine consecutive, symptomatic patients with Waldenstrom macroglobulinemia, of whom 9 were previously untreated. ■ Intervention: 2-Chlorodeoxyadenosine was administered as a continuous intravenous infusion at a dose of 0.1 mg/kg body weight per day for 7 days. Only two courses of 2CdA were given and responding patients were then followed without further treatment. ■ Measurements and Main Results: A total of 17 (59%) patients responded, including all of those who were newly diagnosed and 40% of those who had failed previous therapies. Treatment was well tolerated except for one death in a patient who had presented with severe pancytopenia. With a median follow-up of 7 months, only one responding patient has relapsed. ■ Conclusion: 2-Chlorodeoxyadenosine is a nucleoside analog that was effective in most patients with Waldenstrom macroglobulinemia and was associated with little toxicity.

Twenty-three consecutive patients with Waldenström macroglobulinemia were studied with magnetic resonance (MR) imaging of the spine and computed tomography (CT) of the abdomen and pelvis. MR imaging studies included sagittal T1-weighted and gradient-recalled-echo sequences performed with and without contrast material enhancement. Marrow involvement was identified with MR imaging in 21 of 23 (91%) patients. Diffuse involvement was noted in 13 patients (56%), and a variegated pattern in eight (35%). CT demonstrated enlarged nodes in 10 of 23 (43%) patients. Correlation of MR imaging patterns and presence of adenopathy at CT with standard laboratory values for Waldenström macroglobulinemia revealed an association of the diffuse MR imaging pattern of marrow involvement and the presence of enlarged nodes at CT with more advanced disease. MR imaging of the spine and CT are reliable means of evaluation of disease status in Waldenström macroglobulinemia. They may be employed as additional means in the staging of Waldenström macroglobulinemia and may be helpful in the follow-up of patients with this rare hematologic malignancy.

Forty‐three patients received etoposide, cyclophosphamide, and fractionated total body irradiation before allogeneic marrow transplantation. Fifteen patients had chronic myelogenous leukemia in chronic phase or acute leukemia in first remission (standard risk) and twenty‐eight patients with more advanced disease (high risk). All patients received etoposide 1,500 mg/m2 intravenously on day –8, cyclophosphamide 60 mg/kg/day intravenously on days –7 and –6, and total body irradiation at 170 cGy twice a day on days –3, –2, and –1. During the first 100 days 12 high risk patients (43%) died from causes unrelated to relapse while none of the standard risk patients died. Renal and hepatic dysfunction were also significantly increased during the first 14 days in the high risk group. The addition of 1,500 mg/m2 of etoposide to the cyclophosphamide and total body irradiation was well tolerated for patients with standard risk. However, the regimen was poorly tolerated with high mortality in patients with more advanced disease. © 1992 Wiley‐Liss, Inc. Copyright © 1992 Wiley‐Liss, Inc., A Wiley Company

Purpose: The effects of involved-field radiotherapy were assessed in patients with a solitary plasmacytoma of bone (SBP). Patients and Methods: Forty-five consecutive patients with an SBP received megavoltage irradiation of at least 3,000 cGy. The median age was 53 years, 67% of patients showed a myeloma protein, and uninvolved immunoglobulins (Igs) were preserved in 93% of patients. Results: Permanent control of presenting disease was achieved in all but two patients, but 46% of patients developed multiple myeloma. When it occurred, progression of myeloma occurred within 3 years in two thirds of the patients, suggesting that the extent of disease was understaged at diagnosis. Myeloma protein disappeared in nine patients (30%) whose disease has not yet recurred. The median survival for all patients was 13 years and the myeloma- specific survival fraction at 10 years was 53%. Conclusion: In patients with an SBP, the disappearance of myeloma protein with involved-field radiotherapy predicted long-term disease-free survival and possible cure. Nonsecretory disease and persistent myeloma protein after treatment were adverse prognostic factors for which adjuvant therapy with interferon alfa should be considered.

In this study we measured eight different tumor markers (PSA, PAP, TPA, CEA, Ca 50, Ca 19-9, Ca 125 and Ca 15-3) in 39 patients with prostatic adenocarcinoma and in 90 patients with benign prostatic hyperplasia. We then calculated the sensitivity and specificity for each tumor marker separately and found that only PSA, when we consider as normal value 10 ng/ml, has a sufficiently high sensitivity and specificity. Our conclusion is that only PSA can be used for diagnostic purposes in conjunction with other diagnostic modalities.

Spinal magnetic resonance (MR) imaging was performed in 29 patients with newly diagnosed, untreated multiple myeloma. Nineteen (66%) patients were asymptomatic. Sagittal pre- and postcontrast T1-weighted spin-echo images and gradient-recalled-echo images of the thoracic and lumbosacral spine were obtained. Marrow involvement was identified in 20 (69%) patients. There were three MR patterns: focal lesions in nine patients (31%), diffuse involvement in seven (24%), and an inhomogeneous pattern of tiny lesions on a background of normal marrow in four (14%). A statistically significant correlation between MR imaging patterns of marrow involvement and serum hemoglobin values (one-way, P = .0899; Kruskal-Wallis, P = .0620) and between MR imaging patterns and percentage of marrow plasmacytosis (Kruskal-Wallis, P = .0314) was noted, with patterns of diffuse and focal marrow involvement associated with more abnormal values. Spinal MR imaging in patients with early myeloma may reveal marrow involvement in both symptomatic and asymptomatic patients. Some correlation was found between MR imaging patterns and laboratory indexes of disease.

The potential role of paraneoplastic Cushing's syndrome (CS) was assessed on the clinical course of patients with small cell lung cancer. A retrospective comparison was done of complication and survival rates according to the presence or absence of CS in patients with small cell lung cancer who died within 90 days of initial administration of chemotherapy. The setting was a comprehensive cancer center. Eleven patients with clinical and/or biochemical features of CS were identified from among 90 patients who presented between 1979 and 1989 with previously untreated small cell lung cancer. The group with CS and the control patients were compared in terms of clinicopathologic prognostic factors, treatment, and outcome. Patients with CS were comparable to the control patients in all prognostic factors, including tumor stage and cancer treatment. Eight‐two percent of patients with CS (nine of 11) died within 14 days of initiation of chemotherapy compared with 25% of the control patients (19 of 77). The median survival from initiation of chemotherapy was 12 days for the 11 patients with CS and 27 days for the 77 control patients. In 45% of the patients with CS (five of 11), death was attributed to opportunistic fungal or protozoal infection compared with 8% of control patients (six of 77). paraneoplastic CS is a previously unrecognized adverse prognostic factor for patients with small cell lung cancer. Those with both small cell lung cancer and CS have severe opportunistic infections soon after the initiation of chemotherapy, leading to clinical deterioration and death before antineoplastic benefit from chemotherapy can be achieved. Biochemical control of CS for at least 1 to 2 weeks before initiation of chemotherapy may ameliorate the poor prognosis. Copyright © 1992 American Cancer Society

Intermittent courses of dexamethasone (DEX) were administered to 112 consecutive, previously untreated patients with multiple myeloma (MM). Using criteria based on a 75% or greater reduction of calculated tumor mass, the overall response rate was 43%. Among comparable patients, response rates were approximately 15% less than those observed previously with vincristine-doxorubicin by continuous infusion with intermittent DEX (VAD) and similar to those with melphalan-prednisone. The projected survival times with VAD or DEX were similar. Results indicated that DEX accounted for most of the plasma cell reduction achieved with VAD. Serious complications occurred in 27% of patients treated with VAD, but in only 4% of those who received DEX. In view of the similar outcome with fewer serious complications, DEX provided a simple, effective, and safe primary treatment for a large fraction of patients with MM. Patients who appear most likely to benefit include those with hypercalcemia or pancytopenia, or who require simultaneous radiotherapy for a pathologic fracture. © 1992 by The American Society of Hematology.

There is a wide spectrum of disease among patients with plasma cell myeloma. A small fraction have a localized plasmacytoma of bone that requires specialized techniques for accurate staging, followed by local radiotherapy that may be curative in some patients. Other patients with multiple myeloma may be free of symptoms and the disease is recognized by chance laboratory studies. Some have a prolonged, stable course with little change in disease for many months or years and resemble patients with MGUS. These patients have low serum myeloma protein and are free of focal bone lesions even on MR imaging. Complications are more imminent among other patients with higher levels of myeloma protein and/or bone lesions, who usually require treatment within 2 years after diagnosis. Still other patients with more advanced generalized disease (intermediate tumor mass) or with a pathologic fracture that may be relieved with local radiotherapy usually require even earlier chemotherapy to prevent or treat complications.

We report six female patients with breast cancer who developed dermatomyositis and compare our data with those from other reports. The development of dermatomyositis in two patients led to the discovery of a second primary ovarian carcinoma, whereas the development of dermatomyositis in another two patients led to the discovery of recurrent breast cancer. In three patients the diagnosis of dermatomyositis preceded the diagnosis of breast cancer, while the rest developed dermatomyositis after the diagnosis of breast cancer. A parallel clinical course of dermatomyositis and breast cancer was seen in only one patient. Coexisting dermatomyositis and breast cancer is a rare phenomenon, and dermatomyositis that develops during the course of breast cancer may indicate the occurrence of a second primary malignancy or recurrent breast cancer. The onset of dermatomyositis may precede, coincide with, or follow the diagnosis of breast cancer. The clinical course of dermatomyositis sometimes, but not always, parallels the course of breast cancer. There are no specific clinical or laboratory markers to distinguish patients with dermatomyositis who have malignancy from those without cancer. © 1991.

Cyclosporine and methotrexate at standard doses (15 mg/m2 on day 1 and 10 mg/m2 on days 3, 6, and 11, total 45 mg/m2) are effective in the prophylaxis of actue graft‐vs.‐host disease. However, the combination has significant early toxicities with delayed engraftment, increased mucositis, and hepatotoxicity. We modified the combination by adding single‐dose methylprednisolone and lowered the total dose of methotrexate to 35 mg/m2 (5 mg/m2 on days 1, 3, and 6, and then 10 mg/m2 on days 11 and 18) and then to 20 mg/m2 (5 mg/m2 on days 1, 3, 6, and 11) in an attempt to decrease these side effects in two sequential consecutive groups of patients. We demonstrated that the modified regimens maintained the efficacy with reduced toxicities. The rate of engraftment was comparable to cyclosporine alone and the hepatotoxicity was reduced with reduced doses of methotrexate. Factors such as early immunosuppression of the host, intravenous immunoglobulin, the timing of steroid administration, nucleotide free diet and germ free environment may contribute to the effectiveness of the combination and permit reduction of methotrexate dose. Copyright © 1991 Wiley‐Liss, Inc., A Wiley Company

Twenty-four patients with metastatic and chemotherapy-refractorynonseminomatous germ cell tumors of the testis were treated with various chemotherapy regimens upon failure. Eight of the 24 patients (33 %) are alive and disease free after salvage therapy with a median follow-up of sixteen months. Prognostic factors tested included those known to be predictive for initial response to therapy (clinical stage and degree of elevation of the biomarkers). In addition, time to initiation of salvage therapy and response to initial chemotherapy were assessed as variables. Our data suggest that patients with solitary organ metastases following relapse, and response to initial chemotherapy are favorable predictors for response to salvage treatment. All the patients with solitary organ metastases (5/5 [100 %]) but only 3/19 (16 %) of the patients with multiple metastatic sites were salvaged. Patients with delayed initiation of salvage therapy had a reduced likelihood of achieving a complete remission but this was not statistically significant. The variables identified need to be incorporated into future trials testing the efficacy of salvage therapy for patients with nonseminomatous tumors of the testis. © 1991 Cahners Publishing Company.

We present a rare case of primary renal carcinoid tumor that metastasized to the liver and kidneys. The tumor and the metastases were hypovascular angiographically, did not enhance on CT, and were hyperechoic with a hypoechoic halo on ultrasound. A similar pattern has been seen in a few cases previously reported in the literature. © 1991 Raven Press, Ltd., New York.

Abstract: Cytomegalovirus (CMV) infection is one of the most common causes of morbidity and mortality after allogeneic marrow transplantation. We studied 14 consecutive CMV‐seropositive patients adding ganciclovir (2.5 mg/kg i.v. every 8 hours for 7 days prior to transplant and 6 mg/kg three times a week after neutrophils became > 0.5 times 109/1 and the patients were platelet transfusion‐independent until d 70) to our previous prophylaxis regimen which consisted of intravenous immunoglobulin and acyclovir. The result was compared with 30 consecutive patients whom we studied with our previous regimen. The addition of ganciclovir did not cause any extra toxicities. The incidence of interstitial pneumonitis and cumulative probability of CMV excretion in the first 100 d post‐transplantation was significantly reduced (p = 0.038 and p = 0.035 respectively). The result shows that addition of ganciclovir significantly decreased the incidence of CMV infection in the early post‐transplantation period. © Munksgaard 1991

Objective: To evaluate serum lactate dehydrogenase (LDH) as a prognostic factor in previously untreated patients with multiple myeloma. Design: Study of 391 consecutive patients with uniformly treated multiple myeloma, followed until death in 63% of patients. Setting: Tertiary, referral cancer center. Patients: A total of 391 consecutive, previously untreated, symptomatic patients with various stages of multiple myeloma. Intervention: Various chemotherapy regimens that included doxorubicin or glucocorticoids, or both, with a consistent response rate (53%). Measurements: Outcomes included clinical response based on a 75% reduction of calculated tumor load and survival time from treatment. Univariate and multivariate analyses were used. Main Results: Eleven percent of patients showed a high serum LDH level of more than 5.0 μkat/L (300 U/L). An elevated LDH level was seen more frequently with a rise in the tumor load; an increased level was present in 26% of patients with high tumor mass. A high LDH level was associated with plasma cell leukemia or lymphoma-like clinical features (43%) and with plasma cell hypodiploidy (17%). Only 20% of patients with elevated LDH levels responded to chemotherapy compared with a response rate of 57% for patients with low levels of LDH. Using multivariate analysis, LDH was a significant independent predictor of response (P = 0.001), with an odds ratio of 0.25 (95% Cl, 0.11 to 0.57). A high LDH level was associated with a short median survival (9 months) and showed the highest relative risk (2.63; Cl, 1.75 to 3.95; P= 0.001). Conclusions: Elevation of the LDH level suggests the presence of occult extraosseous disease and high tumor mass. The LDH level is a predictor of a poor prognosis in selected patients who should be considered for early intensive treatment.

Twenty-four patients with metastatic and chemotherapy-refractorynonseminomatous germ cell tumors of the testis were treated with various chemotherapy regimens upon failure. Eight of the 24 patients (33 %) are alive and disease free after salvage therapy with a median follow-up of sixteen months. Prognostic factors tested included those known to be predictive for initial response to therapy (clinical stage and degree of elevation of the biomarkers). In addition, time to initiation of salvage therapy and response to initial chemotherapy were assessed as variables. Our data suggest that patients with solitary organ metastases following relapse, and response to initial chemotherapy are favorable predictors for response to salvage treatment. All the patients with solitary organ metastases (5/5 [100 %]) but only 3/19 (16 %) of the patients with multiple metastatic sites were salvaged. Patients with delayed initiation of salvage therapy had a reduced likelihood of achieving a complete remission but this was not statistically significant. The variables identified need to be incorporated into future trials testing the efficacy of salvage therapy for patients with nonseminomatous tumors of the testis. © 1991 Cahners Publishing Company.

Ras p21 and myc p62 expression has been examined immunohistochemically in seventy specimens of bronchial carcinomas. Both ras and myc oncoproteins were found to be overexpressed at a higher frequency in non small cell carcinomas (squamous cell carcinomas and adenocarcinomas) compared to the small cell carcinoma specimens; however only myc p62 overexpression was found to be statistically significant. Also, ras p21 oncoprotein expression was frequently overexpressed in adenocarcinomas compared to squamous cell carcinomas (p < 0.05). Overexpression of c-myc p62 was found to correlate with poorly differentiated squamous cell carcinomas compared to the well and moderately differentiated tumors. The results of this study indicate that both the ras and myc oncogenes are important in the progression of bronchial carcinomas.

This study was undertaken to assess the value of intravesical interferon alfa-2b treatment in preventing the recurrences of superficial transitional cell carcinoma of the bladder. A total of 30 patients aged from 33 to 78 entered the protocol. The intravesical instillations were performed once a week for 8 weeks. A solution of 10 x 106 IU interferon alfa-2b in 30 ml of normal saline was used. Follow-up ranged from 12 to 28 months. Of the 30 patients, 19 (63.33%) were tumor free at the end of follow-up. Of the remaining 11 patients, 7 presented with recurrent superficial tumors and 4 with invasive bladder tumors. No side effects were noted.

We descibe a patient with adult onset Still's disease (AOSD) who developed meningoencephalitis, sensorimotor peripheral neuropathy and uveitis during the course of disease. An abnormal cerebrospinal fluid and changes on nerve conduction studies substantiated the diagnoses of these unusual complications. The meningoencephalopathy improved before corticosteroid treatment, and the peripheral neuropathy and other features of AOSD have responded to corticosteroids. Our case illustrates the rare occurrence of both cental and peripheral neurological involvement in AOSD.

In 23 mechanically ventilated anuric (six) or oliguric (17) patients (< 16 ml/h of urine output) with severe gas exchange abnormality, we investigated the effect of furosemide on intrapulmonary shunt (Q̇S/Q̇T). Before and after 0.5, 1, and 2 h of IV administration of 200 mg of furosemide, we assessed the intrapulmonary shunt and PaO2 while patients' hemodynamic measurements were monitored. Ventilatory parameters remained constant throughout the study. While the urine output was minimal and no alteration in hemodynamic values was found, the Q̇S/Q̇T decreased from 27.7 ± 2.3 percent (mean ± SEM) at control to 24.3 ± 2.1 percent (p < 0.01) at 0.5 h, 21.7 ± 2.1 percent (P < 0.001) at 1 h, and 18.1 ± 1.8 percent (p < 0.001) at 2 h. The PaO2 showed no significant difference at 0.5 h but rose significantly from 96 ± 14 to 105 ± 14 mm Hg (p < 0.05) and 111 ± 14 mm Hg (p < 0.01) at 1 and 2 h, respectively. Since we observed no changes in hemodynamics, we speculate a direct effect of furosemide in the pulmonary vasculature affecting the ventilation-perfusion mismatch and, therefore, the Q̇S/Q̇T and PaO2.

A case of pure rhabdomyosarcoma of the testis is reported. The origin of these tumors is discussed and it is believed that they are teratomas with rhabdomyoblastic overgrowth of the cells. Prophylactic retroperitoneal lymph node dissection is recommended at the time of the orchiectomy, in those cases where there is no evidence of lymph node metastases.

An unusual presentation of a renal pelvis squamous cell carcinoma is reported; a loin sinus with excessive pyorrhea was the only complaint of a man with a long history of renal calculus disease.

The polymorphism of the third component of the human complement (C3) was investigated in a sample of 1,055 unrelated healthy individuals from nine different areas of Greece. The estimated gene frequencies were: C3S = 0.786 and C3F = 0.211. Three individuals were found to have rare variant C3 types. The allele frequencies resemble those reported for other Caucasian populations. © 1985 S. Karger AG, Basel.

The distribution of phenotypes and gene frequencies of the third component of complement (C3), group-specific component (Gc), haptoglobin (Hp) and transferrin (Tf) were studied in 115 patients with carcinoma of the prostate. The statistical analysis of our findings in comparison to the frequency of these genes in a control group of 155 patients with benign prostatic hyperplasia does not reveal any correlation between the distribution of the Hp and Tf phenotypes and the disease. On the contrary, a statistically significant association was found between carcinoma of prostate and C3(F) and Gc2 genes. The relative risk incidence of this malignancy is 1.56 and 1.81, respectively, for the carriers of these genes suffering from benign prostate hyperplasia.

The distribution of phenotypes and gene frequencies of the 3rd component of complement (C3), group-specific component (G(c)), haptoglobin (Hp) and transferrin (T(f)) were studied in 50 patients with renal adenocarcinoma. The statistical analysis of our findings in comparison to the frequency of these genes in the general population does not reveal any correlation between the distribution of the Hp and Tf phenotypes and the disease. On the contrary, a statistically significant association was found between renal adenocarcinoma and C3(F) and Gc 2 genes. The relative risk incidence of this malignancy is 2.07 and 1.94 respectively for the carriers of these genes. These data indicate that genetic factors, possibly related to the immune mechanisms and calcium metabolism, play a role in the pathogenesis of renal adenocarcinoma.

The distribution of phenotypes and gene frequencies of the C3 component of complement, group-specific component, transferrin and haptoglobin were studied in 155 patients with benign prostatic hyperplasia. A statistical analysis of the findings in comparison with the frequency of these genes in the general population failed to demonstrate any correlation between phenotype distribution and benign prostatic hyperplasia.

The distribution of the phenotypes and the gene frequency of the 3rd fraction of complement (C3), the specific group (Gc), haptoglobin (Hp) and transferrin were studied in 133 patients with transitional cell cancer of the bladder (papillary cancer). Statistical analysis of these results, in comparison with the frequency of these genes in the general population, was unable to demonstrate a correlation between the distribution of these phenotypes and papillary cancer.